Inhibitors of VEGF receptor and HGF receptor signaling

ABSTRACT

The invention relates to the inhibition of VEGF receptor signaling and HGF receptor signaling. The invention provides compounds and methods for inhibiting VEGF receptor signaling and HGF receptor signaling. The invention also provides compositions and methods for treating cell proliferative diseases and conditions.

RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional PatentApplication Ser. No. 60/683,038, filed on May 20, 2005, the contents ofwhich are incorporated herein by reference in its entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to the inhibition of VEGF receptor signaling andHGF receptor signaling. More particularly, the invention relates tocompounds and methods for the inhibition of VEGF receptor signaling andHGF receptor signaling.

2. Summary of the Related Art

Angiogenesis is an important component of certain normal physiologicalprocesses such as embryogenesis and wound healing, but aberrantangiogenesis contributes to some pathological disorders and inparticular to tumor growth.^(1,2) VEGF-A (vascular endothelial growthfactor A) is a key factor promoting neovascularization (angiogenesis) oftumors.³⁻⁷ VEGF induces endothelial cell proliferation and migration bysignaling through two high affinity receptors, the fins-like tyrosinekinase receptor, Flt-1, and the kinase insert domain-containingreceptor, KDR.^(8,9,10). These signaling responses are criticallydependent upon receptor dimerization and activation of intrinsicreceptor tyrosine kinase (RTK) activity. The binding of VEGF as adisulfide-linked homodimer stimulates receptor dimerization andactivation of the RTK domain¹¹. The kinase activity autophosphorylatescytoplasmic receptor tyrosine residues, which then serve as bindingsites for molecules involved in the propagation of a signaling cascade.Although multiple pathways are likely to be elucidated for bothreceptors, KDR signaling is most extensively studied, with a mitogenicresponse suggested to involve ERK-1 and ERK-2 mitogen-activated proteinkinases¹².

Disruption of VEGF receptor signaling is a highly attractive therapeutictarget in cancer, as angiogenesis is a prerequisite for all solid tumorgrowth, and that the mature endothelium remains relatively quiescent(with the exception of the female reproductive system and woundhealing). A number of experimental approaches to inhibiting VEGFsignaling have been examined, including use of neutralizingantibodies^(13,14,15), receptor antagonists¹⁶, soluble receptors¹⁷,antisense constructs¹⁸ and dominant-negative strategies¹⁹.

Despite the attractiveness of anti-angiogenic therapy by VEGF inhibitionalone, several issues may limit this approach. VEGF expression levelscan themselves be elevated by numerous diverse stimuli and perhaps mostimportantly, the hypoxic state of tumors resulting from VEGFrinhibition, can lead to the induction of factors that themselves promotetumor invasion and metastasis thus, potentially undermining the impactof VEGF inhibitors as cancer therapeutics²⁰.

The HGF (hepatocyte growth factor) and the HGF receptor, c-met, areimplicated in the ability of tumor cells to undermine the activity ofVEGF inhibition²⁰. HGF derived from either stromal fibroblastssurrounding tumor cells or expressed from the tumor itself has beensuggested to play a critical role in tumor angiogenesis, invasion andmetastasis^(21,22). For example, invasive growth of certain cancer cellsis drastically enhanced by tumor-stromal interactions involving theHGF/c-Met (HGF receptor) pathway^(23,24,25) HGF, which was originallyidentified as a potent mitogen for hepatocytes^(26,27) is primarilysecreted from stromal cells, and the secreted HGF can promote motilityand invasion of various cancer cells that express c-Met in a paracrinemanner^(28,29,30.) Binding of HGF to c-Met leads to receptorphosphorylation and activation of Ras/mitogen-activated protein kinase(MAPK) signaling pathway, thereby enhancing malignant behaviors ofcancer cells^(30,31). Moreover, stimulation of the HGF/c-met pathwayitself can lead to the induction of VEGF expression, itself contributingdirectly to angiogenic activity³².

Thus, anti-tumor anti-angiogenic strategies or approaches that targetboth VEGF/VEGFr signaling and HGF/c-met signaling may circumvent theability of tumor cells to overcome VEGF inhibition alone and mayrepresent improved cancer therapeutics.

Here we describe small molecules that are potent inhibitors of both theVEGF receptor KDR and the HGF receptor c-met.

BRIEF SUMMARY OF THE INVENTION

The present invention provides new compounds and methods for treatingcell proliferative diseases. The compounds of the invention areinhibitors of protein tyrosine kinase activity. Preferably, thecompounds of the invention are dual function inhibitors, capable ofinhibiting both VEGF and HGF receptor signaling. Accordingly, theinvention provides new inhibitors of protein tyrosine kinase receptorsignaling, such as for example, VEGF receptor signaling and HGF receptorsignaling, including the VEGF receptor KDR and the HGF receptor c-met.

In a first aspect, the invention provides compounds of formula A thatare useful as kinase inhibitors and, therefore, are useful researchtools for the study of the role of kinases in both normal and diseasestates. Preferrably, the invention provides compounds of Formula I thatare useful as inhibitors of VEGF receptor signaling and HGF receptorsignaling and, therefore, are useful research tools for the study of therole of VEGF and HGF in both normal and disease states.

In a first aspect, the invention provides compounds of formula A-0 thatare useful as kinase inhibitors and, therefore, are useful researchtools for the study of the role of kinases in both normal and diseasestates. Preferrably, the invention provides compounds of Formula I thatare useful as inhibitors of VEGF receptor signaling and HGF receptorsignaling and, therefore, are useful research tools for the study of therole of VEGF and HGF in both normal and disease states.

In a third aspect, the invention provides compositions comprising acompound that is an inhibitor of kinase, or an N-oxide, hydrate,solvate, pharmaceutically acceptable salt, prodrug or complexe thereof,and a pharmaceutically acceptable carrier, excipient or diluent.Preferably, the invention provides compositions comprising a compoundthat is an inhibitor of VEGF receptor signaling and HGF receptorsignaling, or an N-oxide, hydrate, solvate, pharmaceutically acceptablesalt, prodrug or complexe thereof, and a pharmaceutically acceptablecarrier, excipient, or diluent. In a preferred embodiment, thecomposition further comprises an additional therapeutic agent.

In a fourth aspect, the invention provides a method of inhibitingkinase, the method comprising contacting the kinase with a compoundaccording to the present invention, or with a composition according tothe present invention. Preferably the invention provides a method ofinhibiting VEGF receptor signaling and HGF receptor signaling, themethod comprising contacting the receptor with a compound according tothe present invention, or with a composition according to the presentinvention. Inhibition of receptor protein kinase activity, preferablyVEGF and HGF receptor signaling, can be in a cell or a multicellularorganism. If in a multicellular organism, the method according to thisaspect of the invention comprises administering to the organism acompound according to the present invention, or a composition accordingto the present invention. Preferably the organism is a mammal, morepreferably a human. In a preferred embodiment, the method furthercomprises contacting the kinase with an additional therapeutic agent.

In a fifth aspect, the invention provides a method of inhibitingproliferative activity of a cell, the method comprising contacting thecell with an effective proliferative inhibiting amount of a compoundaccording to the present invention or a composition thereof. In apreferred embodiment, the method further comprises contacting the cellwith an additional therapeutic agent.

In a sixth aspect, the invention provides a method of treating a cellproliferative disease in a patient, the method comprising administeringto the patient in need of such treatment an effective therapeuticalamount of a compound according to the present invention or a compositionthereof. In a preferred embodiment, the method further comprisesadministering an additional therapeutic agent.

In a seventh aspect, the invention provides a method of inhibiting tumorgrowth in a patient, the method comprising administering to the patientin need thereof an effective therapeutical amount of a compoundaccording to the present invention or a composition thereof. In apreferred embodiment, the method further comprises administering anadditional therapeutic agent.

The foregoing merely summarizes certain aspects of the invention and isnot intended to be limiting in nature. These aspects and other aspectsand embodiments are described more fully below.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The invention provides compounds and methods for inhibiting the VEGFreceptor KDR and the HGF receptor c-met. The invention also providescompositions and methods for treating cell proliferative diseases andconditions. The patent and scientific literature referred to hereinestablishes knowledge that is available to those with skill in the art.The issued patents, applications, and references that are cited hereinare hereby incorporated by reference to the same extent as if each wasspecifically and individually indicated to be incorporated by reference.In the case of inconsistencies, the present disclosure will prevail.

For purposes of the present invention, the following definitions will beused (unless expressly stated otherwise):

The terms “inhibitor of VEGF receptor signaling” and “inhibitor of HGFreceptor signaling” are used to identify a compound having a structureas defined herein, which is capable of interacting with a HGF receptorand a VEGF receptor and inhibiting the activity of HGF and VEGF. In somepreferred embodiments, such reduction of activity is at least about 50%,more preferably at least about 75%, and still more preferably at leastabout 90%.

For simplicity, chemical moieties are defined and referred to throughoutprimarily as univalent chemical moieties (e.g., alkyl, aryl, etc.).Nevertheless, such terms are also used to convey correspondingmultivalent moieties under the appropriate structural circumstancesclear to those skilled in the art. For example, while an “alkyl” moietygenerally refers to a monovalent radical (e.g. CH₃—CH₂—), in certaincircumstances a bivalent linking moiety can be “alkyl,” in which casethose skilled in the art will understand the alkyl to be a divalentradical (e.g., —CH₂—CH₂—), which is equivalent to the term “alkylene.”(Similarly, in circumstances in which a divalent moiety is required andis stated as being “aryl,” those skilled in the art will understand thatthe term “aryl” refers to the corresponding divalent moiety, arylene.)All atoms are understood to have their normal number of valences forbond formation (i.e., 4 for carbon, 3 for N, 2 for O, and 2, 4, or 6 forS, depending on the oxidation state of the S). On occasion a moiety maybe defined, for example, as (A)_(a)-B—, wherein a is 0 or 1. In suchinstances, when a is 0 the moiety is B— and when a is 1 the moiety isA-B—. Also, a number of moieties disclosed herein exist in multipletautomeric forms, all of which are intended to be encompassed by anygiven tautomeric structure.

The term “hydrocarbyl” refers to a straight, branched, or cyclic alkyl,alkenyl, or alkynyl, each as defined herein. A “C₀” hydrocarbyl is usedto refer to a covalent bond. Thus, “C₀-C₃-hydrocarbyl” includes acovalent bond, methyl, ethyl, ethenyl, ethynyl, propyl, propenyl,propynyl, and cyclopropyl.

The term “alkyl” as employed herein refers to straight and branchedchain aliphatic groups having from 1 to 12 carbon atoms, preferably 1-8carbon atoms, and more preferably 1-6 carbon atoms, which is optionallysubstituted with one, two or three substituents. Preferred alkyl groupsinclude, without limitation, methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl. A “C₀” alkyl (as in“C₀-C₃-alkyl”) is a covalent bond (like “C₀” hydrocarbyl).

The term “alkenyl” as used herein means an unsaturated straight orbranched chain aliphatic group with one or more carbon-carbon doublebonds, having from 2 to 12 carbon atoms, preferably 2-8 carbon atoms,and more preferably 2-6 carbon atoms, which is optionally substitutedwith one, two or three substituents. Preferred alkenyl groups include,without limitation, ethenyl, propenyl, butenyl, pentenyl, and hexenyl.

The term “alkynyl” as used herein means an unsaturated straight orbranched chain aliphatic group with one or more carbon-carbon triplebonds, having from 2 to 12 carbon atoms, preferably 2-8 carbon atoms,and more preferably 2-6 carbon atoms, which is optionally substitutedwith one, two or three substituents. Preferred alkynyl groups include,without limitation, ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

An “alkylene,” “alkenylene,” or “alkynylene” group is an alkyl, alkenyl,or alkynyl group, as defined hereinabove, that is positioned between andserves to connect two other chemical groups. Preferred alkylene groupsinclude, without limitation, methylene, ethylene, propylene, andbutylene. Preferred alkenylene groups include, without limitation,ethenylene, propenylene, and butenylene. Preferred alkynylene groupsinclude, without limitation, ethynylene, propynylene, and butynylene.

The term “cycloalkyl” as employed herein includes saturated andpartially unsaturated cyclic hydrocarbon groups having 3 to 12 carbons,preferably 3 to 8 carbons, and more preferably 3 to 6 carbons, whereinthe cycloalkyl group additionally is optionally substituted. Preferredcycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl,cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, andcyclooctyl.

The term “heteroalkyl” refers to an alkyl group, as defined hereinabove,wherein one or more carbon atoms in the chain are replaced by aheteroatom selected from the group consisting of O, S, NH, N-alkyl, SO,SO₂, SO₂NH, or NHSO₂.

An “aryl” group is a C₆-C₁₄ aromatic moiety comprising one to threearomatic rings, which is optionally substituted. Preferably, the arylgroup is a C₆-C₁₀ aryl group. Preferred aryl groups include, withoutlimitation, phenyl, naphthyl, anthracenyl, and fluorenyl. An “aralkyl”or “arylalkyl” group comprises an aryl group covalently linked to analkyl group, either of which may independently be optionally substitutedor unsubstituted. Preferably, the aralkyl group is(C₁-C₆)alk(C₆-C₁₀)aryl, including, without limitation, benzyl,phenethyl, and naphthylmethyl.

A “heterocyclyl” or “heterocyclic” group is a ring structure having fromabout 3 to about 12 atoms, wherein one or more atoms are selected fromthe group consisting of N, O, S, SO, and SO₂. The heterocyclic group isoptionally substituted on carbon at one or more positions. Theheterocyclic group is also independently optionally substituted onnitrogen with alkyl, aryl, aralkyl, alkylcarbonyl, alkylsulfonyl,arylcarbonyl, arylsulfonyl, alkoxycarbonyl, or aralkoxycarbonyl.Preferred heterocyclic groups include, without limitation, epoxy,aziridinyl, tetrahydro furanyl, pyrrolidinyl, piperidinyl, piperazinyl,thiazolidinyl, oxazolidinyl, oxazolidinonyl, and morpholino. In certainpreferred embodiments, the heterocyclic group is fused to an aryl,heteroaryl, or cycloalkyl group. Examples of such fused heterocyclesinclude, without limitation, tetrahydroquinoline and dihydrobenzofuran.Specifically excluded from the scope of this term are compounds where anannular O or S atom is adjacent to another O or S atom.

As used herein, the term “heteroaryl” refers to groups having 5 to 14ring atoms, preferably 5, 6, 9, or 10 ring atoms; having 6, 10, or 14π-electrons shared in a cyclic array; and having, in addition to carbonatoms, from one to three heteroatoms per ring selected from the groupconsisting of N, O, and S. The term “heteroaryl” is also meant toencompass monocyclic and bicyclic groups. For example, a heteroarylgroup may be pyrimidinyl, pyridinyl, benzimidazolyl, thienyl,benzothiazolyl, benzofuranyl and indolinyl. A “heteroaralkyl” or“heteroarylalkyl” group comprises a heteroaryl group covalently linkedto an alkyl group, either of which is independently optionallysubstituted or unsubstituted. Preferred heteroalkyl groups comprise aC₁-C₆ alkyl group and a heteroaryl group having 5, 6, 9, or 10 ringatoms. Specifically excluded from the scope of this term are compoundshaving adjacent annular O and/or S atoms. Examples of preferredheteroaralkyl groups include pyridylmethyl, pyridylethyl,pyrrolylmethyl, pyrrolylethyl, imidazolylmethyl, imidazolylethyl,thiazolylmethyl, and thiazolylethyl. Specifically excluded from thescope of this term are compounds having adjacent annular O and/or Satoms.

For simplicity, reference to a “C_(n)-C_(m)” heterocyclyl or heteroarylmeans a heterocyclyl or heteroaryl having from “n” to “m” annular atoms,where “n” and “m” are integers. Thus, for example, a C₅-C₆-heterocyclylis a 5- or 6-membered ring having at least one heteroatom, and includespyrrolidinyl (C₅) and piperidinyl (C₆); C₆-hetoaryl includes, forexample, pyridyl and pyrimidyl.

An “arylene,” “heteroarylene,” or “heterocyclylene” group is an aryl,heteroaryl, or heterocyclyl group, as defined hereinabove, that ispositioned between and serves to connect two other chemical groups.

Preferred heterocyclyls and heteroaryls include, but are not limited to,acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiophenyl,benzoxazolyl, benzthiazolyl, benztriazolyl, pyridotriazolyl,benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl,4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl,decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl,indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl,isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl,isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl,octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl,piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl,pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl,pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole,pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl,pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl,quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl,tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl,1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl,thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl,1,2,3-triazolyl, 1,2,4-triazolyl, 1,3,4-triazolyl, and xanthenyl.

As employed herein, when a moiety (e.g., cycloalkyl, hydrocarbyl, aryl,heteroaryl, heterocyclic, urea, etc.) is described as “optionallysubstituted” it is meant that the group optionally has from one to four,preferably from one to three, more preferably one or two, non-hydrogensubstituents. Suitable substituents include, without limitation, halo,hydroxy, oxo (e.g., an annular —CH— substituted with oxo is —C(O)—)nitro, halohydrocarbyl, hydrocarbyl, aryl, aralkyl, alkoxy, aryloxy,amino, acylamino, alkylcarbamoyl, arylcarbamoyl, aminoalkyl, acyl,carboxy, hydroxyalkyl, alkanesulfonyl, arenesulfonyl, alkanesulfonamido,arenesulfonamido, aralkylsulfonamido, alkylcarbonyl, acyloxy, cyano, andureido groups. Preferred substituents, which are themselves not furthersubstituted (unless expressly stated otherwise) are:

-   -   (a) halo, hydroxy, cyano, oxo, carboxy, formyl, nitro, amino,        amidino, guanidino,    -   (b) C₁-C₅ alkyl or alkenyl or arylalkyl imino, carbamoyl, azido,        carboxamido, mercapto, hydroxy, hydroxyalkyl, alkylaryl,        arylalkyl, C₁-C₈ alkyl, C₁-C₈ alkenyl, C₁-C₈ alkoxy, C₁-C₈        alkoxycarbonyl, aryloxycarbonyl, C₂-C₈ acyl, C₂-C₈ acylamino,        C₁-C₈ alkylthio, arylalkylthio, arylthio, C₁-C₈ alkylsulfinyl,        arylalkylsulfinyl, arylsulfinyl, C₁-C₈ alkylsulfonyl,        arylalkylsulfonyl, arylsulfonyl, C₀-C₆ N-alkyl carbamoyl, C₂-C₁₅        N,N-dialkylcarbamoyl, C₃-C₇ cycloalkyl, aroyl, aryloxy,        arylalkyl ether, aryl, aryl fused to a cycloalkyl or heterocycle        or another aryl ring, C₃-C₇ heterocycle, C₅-C₁₄ heteroaryl, or        any of these rings fused or spiro-fused to a cycloalkyl,        heterocyclyl, or aryl, wherein each of the foregoing is further        optionally substituted with one more moieties listed in (a),        above; and    -   (c) —(CH₂)_(s)—NR³⁰R³¹, wherein s is from 0 (in which case the        nitrogen is directly bonded to the moiety that is substituted)        to 6, and R³⁰ and R³¹ are each independently hydrogen, cyano,        oxo, carboxamido, amidino, C₁-C₈ hydroxyalkyl, C₁-C₃ alkylaryl,        aryl-C₁-C₃ alkyl, C₁-C₈ alkyl, C₁-C₈ alkenyl, C₁-C₈ alkoxy,        C₁-C₈ alkoxycarbonyl, aryloxycarbonyl, aryl-C₁-C₃        alkoxycarbonyl, C₂-C₈ acyl, C₁-C₈ alkylsulfonyl,        arylalkylsulfonyl, arylsulfonyl, aroyl, aryl, cycloalkyl,        heterocyclyl, or heteroaryl, wherein each of the foregoing is        further optionally substituted with one more moieties listed in        (a), above; or        -   R³⁰ and R³¹ taken together with the N to which they are            attached form a heterocyclyl or heteroaryl, each of which is            optionally substituted with from 1 to 3 substituents from            (a), above.

Especially preferred substituents on alkyl groups include halogen,hydroxy, alkoxy and alkylamine.

Especially preferred substituents or ring groups, such as aryl,heteroaryl, cycloalkyl and heterocyclyl, include halogen, alkoxy andalkyl.

A “halohydrocarbyl” is a hydrocarbyl moiety in which from one to allhydrogens have been replaced with one or more halo.

The term “halogen” or “halo” as employed herein refers to chlorine,bromine, fluorine, or iodine. As herein employed, the term “acyl” refersto an alkylcarbonyl or arylcarbonyl substituent. The term “acylamino”refers to an amide group attached at the nitrogen atom (i.e., R—CO—NH—).The term “carbamoyl” refers to an amide group attached at the carbonylcarbon atom (i.e., NH₂—CO—). The nitrogen atom of an acylamino orcarbamoyl substituent is additionally substituted. The term“sulfonamido” refers to a sulfonamide substituent attached by either thesulfur or the nitrogen atom. The term “amino” is meant to include NH₂,alkylamino, arylamino, and cyclic amino groups. The term “ureido” asemployed herein refers to a substituted or unsubstituted urea moiety.

The term “radical” as used herein means a chemical moiety comprising oneor more unpaired electrons.

A moiety that is substituted is one in which one or more hydrogens havebeen independently replaced with another chemical substituent. As anon-limiting example, substituted phenyls include 2-fluorophenyl,3,4-dichlorophenyl, 3-chloro-4-fluoro-phenyl, 2-fluoro-3-propylphenyl.As another non-limiting example, substituted n-octyls include2,4-dimethyl-5-ethyl-octyl and 3-cyclopentyl-octyl. Included within thisdefinition are methylenes (—CH₂—) substituted with oxygen to formcarbonyl —CO—).

An “unsubstituted” moiety as defined above (e.g., unsubstitutedcycloalkyl, unsubstituted heteroaryl, etc.) means that moiety as definedabove that does not have any of the optional substituents for which thedefinition of the moiety (above) otherwise provides. Thus, for example,while an “aryl” includes phenyl and phenyl substituted with a halo,“unsubstituted aryl” does not include phenyl substituted with a halo.

Examples of kinases that are inhibited by the compounds and compositionsdescribed herein and against which the methods described herein areuseful include, but are not limited to, c-Met and KDR.

Depending on the particular condition, or disease, to be treated,additional therapeutic agents, which could be normally administered totreat that condition, may also be present in the compositions of thisinvention. In other words, compounds of this invention can beadministered as the sole pharmaceutical agent or in combination with oneor more other additional therapeutic (pharmaceutical) agents where thecombination causes no unacceptable adverse effects. This may be ofparticular relevance for the treatment of hyper-proliferative diseasessuch as cancer. In this instance, the compound of this invention can becombined with known cytotoxic agents, signal transduction inhibitors, orwith other anti-cancer agents, as well as with admixtures andcombinations thereof. As used herein, additional therapeutic agents thatare normally administered to treat a particular disease, or condition,are known as “appropriate for the disease, or condition, being treated”.As used herein, “additional therapeutic agents” is meant to includechemotherapeutic agents and other anti-proliferative agents.

For example, chemotherapeutic agents or other anti-proliferative agentsmay be combined with the compounds of this invention to treatproliferative disease or cancer. Examples of chemotherapeutic agents orother anti-proliferative agents include HDAC inhibitors including, butare not limited to, SAHA, MS-275, MG0103, and those described in WO2006/010264, WO 03/024448, WO 2004/069823, US 2006/0058298, US2005/0288282, WO 00/71703, WO 01/38322, WO 01/70675, WO 03/006652, WO2004/035525, WO 2005/030705, WO 2005/092899, and demethylating agentsincluding, but not limited to, 5-aza-dC, Vidaza and Decitabine and thosedescribed in U.S. Pat. No. 6,268,137, U.S. Pat. No. 5,578,716, U.S. Pat.No. 5,919,772, U.S. Pat. No. 6,054,439, U.S. Pat. No. 6,184,211, U.S.Pat. No. 6,020,318, U.S. Pat. No. 6,066,625, U.S. Pat. No. 6,506,735,U.S. Pat. No. 6,221,849, U.S. Pat. No. 6,953,783, U.S. Ser. No.11/393,380 and PCT/US2006/001791.

In another embodiment of the present invention, for example,chemotherapeutic agents or other anti-proliferative agents may becombined with the compounds of this invention to treat proliferativediseases and cancer. Examples of known chemotherapeutic agents include,but are not limited to, for example, other therapies or anticanceragents that may be used in combination with the inventive anticanceragents of the present invention and include surgery, radiotherapy (inbut a few examples, gamma-radiation, neutron beam radiotherapy, electronbeam radiotherapy, proton therapy, brachytherapy, and systemicradioactive isotopes, to name a few), endocrine therapy, taxanes (taxol,taxotere etc), platinum derivatives, biologic response modifiers(interferons, interleukins, and tumor necrosis factor (TNF), TRAILreceptor targeting agents, to name a few), hyperthermia and cryotherapy,agents to attenuate any adverse effects (e.g., antiemetics), and otherapproved chemotherapeutic drugs, including, but not limited to,alkylating drugs (mechlorethamine, chlorambucil, Cyclophosphamide,Melphalan, Ifosfamide), antimetabolites (Methotrexate, Pemetrexed etc),purine antagonists and pyrimidine antagonists (6-Mercaptopurine,5-Fluorouracil, Cytarabile, Gemcitabine), spindle poisons (Vinblastine,Vincristine, Vinorelbine, Paclitaxel), podophyllotoxins (Etoposide,Irinotecan, Topotecan), antibiotics (Doxorubicin, Bleomycin, Mitomycin),nitrosoureas (Carmustine, Lomustine), inorganic ions (Cisplatin,Carboplatin), Cell cycle inhibitors (KSP mitotic kinesin inhibitors,CENP-E and CDK inhibitors), enzymes (Asparaginase), and hormones(Tamoxifen, Leuprolide, Flutamide, and Megestrol), Gleevec™, adriamycin,dexamethasone, and cyclophosphamide. Antiangiogenic agents (Avastin andothers). Kinase inhibitors (Imatinib (Gleevec), Sutent, Nexavar,Erbitux, Herceptin, Tarceva, Iressa and others). Agents inhibiting oractivating cancer pathways such as the mTOR, HIF (hypoxia inducedfactor) pathways and others. For a more comprehensive discussion ofupdated cancer therapies see, http://www.nci.nih.gov/, a list of the FDAapproved oncology drugs athttp://www.fda.gov/cder/cancer/druglistframe.htm, and The Merck Manual,Eighteenth Ed. 2006, the entire contents of which are herebyincorporated by reference.

In another embodiment, the compounds of the present invention can becombined with cytotoxic anti-cancer agents. Examples of such agents canbe found in the 13th Edition of the Merck Index (2001) These agentsinclude, by no way of limitation, asparaginase, bleomycin, carboplatin,carmustine, chlorambucil, cisplatin, colaspase, cyclophosphamide,cytarabine, dacarbazine, dactinomycin, daunorubicin, doxorubicin(adriamycine), epirubicin, etoposide, 5-fluorouracil,hexamethylmelamine, hydroxyurea, ifosfamide, irinotecan, leucovorin,lomustine, mechlorethamine, 6-mercaptopurine, mesna, methotrexate,mitomycin C, mitoxantrone, prednisolone, prednisone, procarbazine,raloxifen, streptozocin, tamoxifen, thioguanine, topotecan, vinblastine,vincristine, and vindesine.

Other cytotoxic drugs suitable for use with the compounds of theinvention include, but are not limited to, those compounds acknowledgedto be used in the treatment of neoplastic diseases, such as those forexample in Goodman and Gilman's The Pharmacological Basis ofTherapeutics (Ninth Edition, 1996, McGraw-Hill). These agents include,by no way of limitation, aminoglutethimide, L-asparaginase,azathioprine, 5-azacytidine cladribine, busulfan, diethylstilbestrol,2′,2′-difluorodeoxycytidine, docetaxel, erythrohydroxynonyladenine,ethinyl estradiol, 5-fluorodeoxyuridine, 5-fluorodeoxyuridinemonophosphate, fludarabine phosphate, fluoxymesterone, flutamide,hydroxyprogesterone caproate, idarubicin, interferon,medroxyprogesterone acetate, megestrol acetate, melphalan, mitotane,paclitaxel, pentostatin, N-phosphonoacetyl-L-aspartate (PALA),plicamycin, semustine, teniposide, testosterone propionate, thiotepa,trimethylmelamine, uridine, and vinorelbine.

Other cytotoxic anti-cancer agents suitable for use in combination withthe compounds of the invention also include newly discovered cytotoxicprinciples such as oxaliplatin, gemcitabine, capecitabine, epothiloneand its natural or synthetic derivatives, temozolomide (Quinn et al., J.Clin. Oncology 2003, 21(4), 646-651), tositumomab (Bexxar), trabedectin(Vidal et al., Proceedings of the American Society for Clinical Oncology2004, 23, abstract 3181), and the inhibitors of the kinesin spindleprotein Eg5 (Wood et al., Curr. Opin. Pharmacol. 2001, 1, 370-377).

In another embodiment, the compounds of the present invention can becombined with other signal transduction inhibitors. Of particularinterest are signal transduction inhibitors which target the EGFRfamily, such as EGFR, HER-2, and HER-4 (Raymond et al., Drugs 2000, 60(Suppl.1), 15-23; Harari et al., Oncogene 2000, 19 (53), 6102-6114), andtheir respective ligands. Examples of such agents include, by no way oflimitation, antibody therapies such as Herceptin (trastuzumab), Erbitux(cetuximab), and pertuzumab. Examples of such therapies also include, byno way of limitation, small-molecule kinase inhibitors such asZD-1839/Iressa (Baselga et al., Drugs 2000, 60 (Suppl. 1), 33-40),OSI-774/Tarceva (Pollack et al. J. Pharm. Exp. Ther. 1999, 291(2),739-748), CI-1033 (Bridges, Curr. Med. Chem. 1999, 6, 825-843), GW-2016(Lackey et al., 92nd AACR Meeting, New Orleans, Mar. 24-28, 2001,abstract 4582), CP-724,714 (Jani et al., Proceedings of the AmericanSociety for Clinical Oncology 2004, 23, abstract 3122), HKI-272(Rabindran et al., Cancer Res. 2004, 64, 3958-3965), and EKB-569(Greenberger et al., 11th NCI-EORTC-AACR Symposium on New Drugs inCancer Therapy, Amsterdam, Nov. 7-10, 2000, abstract 388).

In another embodiment, the compounds of the present invention can becombined with other signal transduction inhibitors targeting receptorkinases of the split-kinase domain families (VEGFR, FGFR, PDGFR, flt-3,c-kit, c-fms, and the like), and their respective ligands. These agentsinclude, by no way of limitation, antibodies such as Avastin(bevacizumab). These agents also include, by no way of limitation,small-molecule inhibitors such as STI-571/Gleevec (Zvelebil, Curr. Opin.Oncol., Endocr. Metab. Invest. Drugs 2000, 2(1), 74-82), PTK-787 (Woodet al., Cancer Res. 2000, 60(8), 2178-2189), SU-11248 (Demetri et al.,Proceedings of the American Society for Clinical Oncology 2004, 23,abstract 3001), ZD-6474 (Hennequin et al., 92nd AACR Meeting, NewOrleans, Mar. 24-28, 2001, abstract 3152), AG-13736 (Herbst et al.,Clin. Cancer Res. 2003, 9, 16 (suppl 1), abstract C253), KRN-951(Taguchi et al., 95<th> AACR Meeting, Orlando, Fla., 2004, abstract2575), CP-547,632 (Beebe et al., Cancer Res. 2003, 63, 7301-7309),CP-673,451 (Roberts et al., Proceedings of the American Association ofCancer Research 2004, 45, abstract 3989), CHIR-258 (Lee et al.,Proceedings of the American Association of Cancer Research 2004, 45,abstract 2130), MLN-518 (Shen et al., Blood 2003, 102, 11, abstract476), and AZD-2171 (Hennequin et al., Proceedings of the AmericanAssociation of Cancer Research 2004, 45, abstract 4539).

In another embodiment, the compounds of the present invention can becombined with inhibitors of the Raf/MEK/ERK transduction pathway (Avruchet al., Recent Prog. Horm. Res. 2001, 56, 127-155), or the PKB (akt)pathway (Lawlor et al., J. Cell Sci. 2001, 114, 2903-2910). Theseinclude, by no way of limitation, PD-325901 (Sebolt-Leopold et al.,Proceedings of the American Association of Cancer Research 2004, 45,abstract 4003), and ARRY-142886 (Wallace et al., Proceedings of theAmerican Association of Cancer Research 2004, 45, abstract 3891).

In another embodiment, the compounds of the present invention can becombined with inhibitors of histone deacetylase. Examples of such agentsinclude, by no way of limitation, suberoylanilide hydroxamic acid(SAHA), LAQ-824 (Ottmann et al., Proceedings of the American Society forClinical Oncology 2004, 23, abstract 3024), LBH-589 (Beck et al.,Proceedings of the American Society for Clinical Oncology 2004, 23,abstract 3025), MS-275 (Ryan et al., Proceedings of the AmericanAssociation of Cancer Research 2004, 45, abstract 2452), FR-901228(Piekarz et al., Proceedings of the American Society for ClinicalOncology 2004, 23, abstract 3028) and MGCD0103 (U.S. Pat. No.6,897,220).

In another embodiment, the compounds of the present invention can becombined with other anti-cancer agents such as proteasome inhibitors,and m-TOR inhibitors. These include, by no way of limitation, bortezomib(Mackay et al., Proceedings of the American Society for ClinicalOncology 2004, 23, Abstract 3109), and CCI-779 (Wu et al., Proceedingsof the American Association of Cancer Research 2004, 45, abstract 3849).The compounds of the present invention can be combined with otheranti-cancer agents such as topoisomerase inhibitors, including but notlimited to camptothecin.

Those additional agents may be administered separately from thecompound-containing composition, as part of a multiple dosage regimen.Alternatively, those agents may be part of a single dosage form, mixedtogether with the compound of this invention in a single composition. Ifadministered as part of a multiple dosage regimen, the two active agentsmay be submitted simultaneously, sequentially or within a period of timefrom one another which would result in the desired activity of theagents.

The amount of both the compound and the additional therapeutic agent (inthose compositions which comprise an additional therapeutic agent asdescribed above) that may be combined with the carrier materials toproduce a single dosage form will vary depending upon the host treatedand the particular mode of administration.

In those compositions which comprise an additional therapeutic agent,that additional therapeutic agent and the compound of this invention mayact synergistically.

Throughout the specification, preferred embodiments of one or morechemical substituents are identified. Also preferred are combinations ofpreferred embodiments, for example, preferred embodiments of E andpreferred embodiments of T. Furthermore, compounds excluded from any oneparticular genus of compounds (e.g., through a proviso clause) areintended to be excluded from the scope of the invention entirely,including from other disclosed genera, unless expressly stated to thecontrary.

Compounds

In the first aspect, the invention comprises compounds of formula (A),that are inhibitors of VEGF receptor signaling and HGF receptorsignaling:

and N-oxides, hydrates, solvates, pharmaceutically acceptable salts,prodrugs and complexes thereof, wherein

-   T is selected from the group consisting of arylalkyl, cycloalkyl,    heterocyclyl, aryl and heteroaryl, wherein each of said arylalkyl,    cycloalkyl, heterocyclyl, aryl and heteroaryl is optionally    substituted with 1 to 3 independently selected R²⁰;-   each R²⁰ is independently selected from the group consisting of —H,    halogen, trihalomethyl, —CN, —NO₂, —NH₂, —OR¹⁷, —OCF₃, —NR¹⁷R¹⁸,    —S(O)₀₋₂R¹⁷, —S(O)₂NR¹⁷R¹⁷, —C(O)OR¹⁷, —C(O)NR¹⁷R¹⁷, —N(R¹⁷)SO₂R¹⁷,    —N(R¹⁷)C(O)R¹⁷, —N(R¹⁷)C(O)OR¹⁷, —C(O)R¹⁷, —C(O)SR¹⁷, C₁-C₄ alkoxy,    C₁-C₄ alkylthio, —O(CH₂)_(n)aryl, —O(CH₂)_(n)heteroaryl,    —(CH₂)₀₋₅(aryl), —(CH₂)₀₋₅(heteroaryl), C₁-C₆ alkyl, C₂-C₆ alkenyl,    C₂-C₆ alkynyl, —CH₂(CH₂)₀₋₄-T², an optionally substituted C₁₋₄    alkylcarbonyl, C₁₋₄ alkoxy, an amino optionally substituted by C₁₋₄    alkyl optionally substituted by C₁₋₄ alkoxy and a saturated or    unsaturated three- to seven-membered carboxyclic or heterocyclic    group, wherein T² is selected from the group consisting of —OH,    —OMe, —OEt, —NH₂, —NHMe, —NMe₂, —NHEt and —NEt₂, and wherein the    aryl, heteroaryl, C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl are    optionally substituted;-   W is selected from the group consisting of O, S, NH and NMe;-   Z is selected from the group consisting of O, or S and NH;-   X and X¹ are independently selected from the group consisting of H,    C₁-C₆ alkyl, halo, cyano, or nitro, wherein C₁-C₆ alkyl is    optionally substituted, or-   X and X¹ taken together with the atom to which they are attached,    form a C₃-C₇ cycloalkyl;-   R¹, R², R³ and R⁴ independently represent hydrogen, halo,    trihalomethyl, —CN, —NO₂, —NH₂, —OR¹⁷, —NR¹⁷R¹⁸, —C(O)OR¹⁷,    —C(O)R¹⁷, C₁-C₄ alkoxy, C₁-C₄ alkylthio, C₁-C₆ alkyl, C₂-C₆ alkenyl    or C₂-C₆ alkynyl, wherein C₁-C₆ alkyl, C₂-C₆ alkenyl and C₂-C₆    alkynyl are optionally substituted;-   R¹⁷ is selected from the group consisting of H and R¹⁸;-   R¹⁸ is selected from the group consisting of a (C₁-C₆)alkyl, an    aryl, a aryl(C₁-C₆)alkyl, a heterocyclyl and a    heterocyclyl(C₁-C₆)alkyl, each of which is optionally substituted,    or-   R¹⁷ and R¹⁸, taken together with a common nitrogen to which they are    attached, form an optionally substituted five- to seven-membered    heterocyclyl, the optionally substituted five- to seven-membered    heterocyclyl optionally containing at least one additional annular    heteroatom selected from the group consisting of N, O, S and P;-   R¹⁶ is selected from the group consisting of —H, —CN,    —(CH₂)₀₋₅(aryl), —(CH₂)₀₋₅(heteroaryl), C₁-C₆ alkyl, C₂-C₆ alkenyl,    C₂-C₆ alkynyl, —CH₂(CH₂)₀₋₄-T², an optionally substituted C₁₋₄    alkylcarbonyl, and a saturated or unsaturated three- to    seven-membered carboxyclic or heterocyclic group, wherein T² is    selected from the group consisting of —OH, —OMe, —OEt, —NH₂, —NHMe,    —NMe₂, —NHEt and —NEt₂, and wherein the aryl, heteroaryl, C₁-C₆    alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl are optionally substituted;-   Q is selected from the group consisting of CH₂, O, S, N(H), N(C₁-C₆    alkyl), N—Y-(aryl), —N—OMe, —NCH₂OMe and —N-Bn;-   D is selected from the group consisting of C-E and N;-   L is N, or CR, wherein R is selected from the group consisting of    —H, halo, —CN, C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl,    wherein C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl are optionally    substituted; and-   E is selected from the group consisting of E¹, E² and E³, wherein-   E¹ is selected from the group consisting of —H, halogen, nitro,    azido, C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, —C(O)NR⁴²R⁴³, —Y—NR⁴²R⁴³,    —NR⁴²C(═O)R⁴³, —SO₂R⁴², —SO₂NR⁴²R⁴³, —NR³⁷SO₄₂R⁴², —NR³⁷SO₂NR⁴²R⁴³,    —C(═N—OR⁴²)R⁴³, —C(═NR⁴²)R⁴³, —NR³⁷C(═NR⁴²)R⁴³, —C(═NR⁴²)NR³⁷R⁴³,    —NR³⁷C(═NR⁴²)NR³⁷R⁴³, —C(O)R⁴², —CO₂R⁴², —C(O)(heterocyclyl),    —C(O)(C₆-C₁₀ aryl), —C(O)(heteroaryl), —Y—(C₆-C₁₀ aryl),    —Y-(heteroaryl), —Y-(5-10 membered heterocyclic), —NR^(6a)R^(6b),    —NR^(6a)SO₂R^(6b), —NR^(6a)C(O)R^(6b), —OC(O)R^(6b),    —NR^(6a)C(O)OR^(6b), —OC(O)NR^(6a)R^(6b), —OR^(6a), SR^(6a),    —S(O)R^(6a), —SO₂R^(6a), —SO₃R^(6a), —SO₂NR^(6a)R^(6b), —SO₂NR⁴²R⁴³,    —COR^(6a), —CO₂R^(6a), —CONR^(6a)R^(6b), —(C₁-C₄)fluoroalkyl,    —(C₁-C₄)fluoroalkoxy, —(CZ³Z⁴)_(a)CN, wherein n is an integer    ranging from 0 to 6, and the aforementioned E¹ groups other than —H    and halogen are optionally substituted by 1 to 5 independently    selected R³⁸, or E¹ is selected from a moiety selected from the    group consisting of —(CZ³Z₄)_(a)-aryl, —(CZ³Z⁴)_(a)-heterocycle,    (C₂-C₆)alkynyl, —(CZ³Z⁴)_(a)—(C₃-C₆)cycloalkyl,    —(CZ³Z⁴)_(a)-(C₅-C₆)cycloalkenyl, (C₂-C₆) alkenyl and (C₁-C₆)alkyl,    which is optionally substituted with 1 to 3 independently selected    Y² groups, where a is 0, 1, 2, or 3, and wherein when a is 2 or 3,    the CZ³Z⁴ units may be the same or different; wherein-   each R³⁸ is independently selected from halo, cyano, nitro,    trifluoromethoxy, trifluoromethyl, azido, —C(O)R⁴⁰, —C(O)OR⁴⁰,    —OC(O)R⁴⁰, —OC(O)OR⁴⁰, —NR³⁶C(O)R³⁹, —C(O)NR³⁶R³⁹, —NR³⁶R³⁹, —OR³⁷,    —SO₂NR³⁶R³⁹, C₁-C₆ alkyl, —(CH₂)_(j)O(CH₂)_(i)NR³⁶R³⁹,    —(CH₂)_(n)O(CH₂)_(i)OR³⁷, —(CH₂)_(n)OR³⁷, —S(O)_(j)(C₁-C₆ alkyl),    —(CH₂)_(n)(C₆-C₁₀ aryl), —(CH₂)_(n)(C₅-C₁₀ heteroaryl),    —(CH₂)_(n)(5-10 membered heterocyclyl); —C(O)(CH₂)_(n)(C₆-C₁₀ aryl),    —(CH₂)_(n)O(CH₂)_(j)(C₆-C₁₀ aryl), —(CH₂)_(n)O(CH₂)_(i)(5-10    membered heterocyclyl), —C(O)(CH₂)_(n)(5-10 membered heterocyclyl),    —(CH₂)_(j)NR³⁹(CH₂)_(i)NR³⁶R³⁹, —(CH₂)_(j)NR³⁹CH₂C(O)NR³⁶R³⁹,    —(CH₂)_(j)NR³⁹(CH₂)_(i)NR³⁷C(O)R⁴⁰,    —(CH₂)_(j)NR³⁹(CH₂)_(n)O(CH₂)_(i)OR³⁷,    —(CH₂)_(j)NR³⁹(CH₂)_(i)S(O)_(j)(C₁-C₆ alkyl),    —(CH₂)_(j)NR³⁹(CH₂)_(n)R³⁶, —SO₂(CH₂)_(n)(C₆-C₁₀ aryl),    —SO₂(CH₂)_(n)(5-10 membered heterocyclyl), —(CH₂)_(n)NR³⁶R³⁹,    —NR³⁷SO₂NR³⁶R³⁹, SO₂R³⁶, C₂-C₆ alkenyl, C₃-C₁₀ cycloalkyl and C₁-C₆    alkylamino, wherein j is an integer ranging from 0 to 2, n is an    integer ranging from 0 to 6, i is an integer ranging from 0 to 6,    the —(CH₂)_(i)— and —(CH₂)_(n)— moieties of the foregoing R³⁸ groups    optionally include a carbon-carbon double or triple bond where n is    an integer between 2 and 6, and the alkyl, aryl, heteroaryl and    heterocyclyl moieties of the foregoing R³⁸ groups are optionally    substituted by one or more substituents independently selected from    the group consisting of halo, cyano, nitro, trifluoromethyl, azido,    —OH, —C(O)R⁴⁰, —C(O)OR⁴⁰, —OC(O)R⁴⁰, —OC(O)OR⁴⁰, —NR³⁶C(O)R³⁹,    —C(O)NR³⁶R³⁹, —(CH₂)_(n)NR³⁶R³⁹, C₁-C₆ alkyl, C₃-C₁₀cycloalkyl,    —(CH₂)_(n)(C₆-C₁₀ aryl), —(CH₂)_(n)(5-10 membered heterocyclyl),    —(CH₂)_(n)O(CH₂)_(i)OR³⁷, and —(CH₂)_(n)OR³⁷, wherein n is an    integer ranging from 0 to 6 and i is an integer ranging from 2 to 6;-   each R⁴² and R⁴³ is independently selected from the group consisting    of H, C₁-C₆ alkyl, C₁-C₆ heteroalkyl, —Y—(C₃-C₁₀ cycloalkyl),    —Y—(C₆-C₁₀ aryl), —Y—(C₆-C₁₀ heteroaryl), —Y-(5-10 membered    heterocyclic), —Y—O—Y¹—OR³⁷, —Y¹—CO₂—R³⁷, and —Y—OR³⁷, wherein the    alkyl, heteroalkyl, cycloalkyl, aryl, heteroaryl and heterocyclic    moieties of the foregoing R⁴² and R⁴³ groups are optionally    substituted by 1 or more substituents independently selected from    R⁴⁴, wherein-   Y is a bond or is —(C(R³⁷)(H))_(n),-   n is an integer ranging from 1 to 6, and-   Y¹ is —(C(R³⁷)(H))_(n), or-   R⁴² and R⁴³ taken together with the nitrogen to which they are    attached form a C₅-C₉ heterocyclyl ring or a heteroaryl ring,    wherein said ring is optionally substituted by 1 to 5 independently    selected R⁴⁴ substituents, with the proviso that R⁴² and R⁴³ are not    both bonded to the nitrogen directly through an oxygen;-   each R⁴⁴ is independently selected from the group consisting of    halo, cyano, nitro, trifluoromethoxy, trifluoromethyl, azido,    —C(O)R⁴⁰, —C(O)OR⁴⁰, —OC(O)R⁴⁰, —OC(O)OR⁴⁰, —NR³⁶C(O)R³⁹,    —C(O)NR³⁶R³⁹, —NR³⁶R³⁹, —OR³⁷, —SO₂NR³⁶R³⁹, —SO₂R³⁶, —NR³⁶SO₂R³⁹,    —NR³⁶SO₂NR³⁷R⁴¹, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀    cycloalkyl, —C₁-C₆ alkylamino, —(CH₂)_(j)O(CH₂)_(i)NR³⁶R³⁹,    —(CH₂)_(n)O(CH₂)_(i)OR³⁷, —(CH₂)_(n)OR³⁷, —S(O)_(j)(C₁-C₆ alkyl),    —(CH₂)_(n)(C₆-C₁₀ aryl), —(CH₂)_(n)(5-10 membered heterocyclic),    —C(O)(CH₂)_(n)(C₆-C₁₀ aryl), —(CH₂)_(n)O(CH₂)_(j)(C₆-C₁₀ aryl),    —(CH₂)_(n)O(CH₂)_(i)(5 to 10 membered heterocyclic),    —C(O)(CH₂)_(n)(5 to 10 membered heterocyclic),    —(CH₂)_(j)NR³⁹(CH₂)_(i)NR³⁶R³⁹, —(CH₂)_(j)NR³⁹CH₂C(O)NR³⁶R³⁹,    —(CH₂)_(j)NR³⁹(CH₂)_(i)NR³⁷C(O)R⁴⁰,    —(CH₂)_(j)NR³⁹(CH₂)_(i)O(CH₂)_(i)OR³⁷,    —(CH₂)_(j)NR³⁹(CH₂)_(i)S(O)_(j)(C₁-C₆ alkyl),    —(CH₂)_(j)NR³⁹(CH₂)_(n)R³⁶, —SO₂(CH₂)_(n)(C₆-C₁₀ aryl), and    —SO₂(CH₂)_(n)(5 to 10 membered heterocyclic) wherein, j is an    integer from 0 to 2, n is an integer from 0 to 6 and i is an integer    ranging from 2 to 6, the —(CH₂)_(i)— and —(CH₂)_(n1)— moieties of    the foregoing R⁴⁴ groups optionally include a carbon-carbon double    or triple bond wherein n is an integer from 2 to 6, and the alkyl,    aryl and heterocyclic moieties of the foregoing R⁴⁴ groups are    optionally substituted by 1 or more substituents independently    selected from the group consisting of halo, cyano, nitro,    trifluoromethyl, azido, —OH, —C(O)R⁴⁰, —C(O)OR⁴⁰, —OC(O)R⁴⁰,    —OC(O)OR⁴⁰, —NR³⁶C(O)R³⁹, —C(O)NR³⁶R³⁹, —(CH₂)_(n)NR³⁶R³⁹, —SO₂R³⁶,    —SO₂NR³⁶R³⁹, C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, —(CH₂)_(n)(C₆-C₁₀    aryl), —(CH₂)_(n)(5 to 10 membered heterocyclic),    —(CH₂)_(n)O(CH₂)_(i)OR³⁷ and —(CH₂)_(n)OR³⁷, wherein n is an integer    from 0 to 6 and i is an integer from 2 to 6; and-   each R⁴⁰ is independently selected from H, C₁-C₁₀ alkyl,    —(CH₂)_(n)(C₆-C₁₀ aryl), C₃-C₁₀ cycloalkyl, and —(CH₂)_(n)(5-10    membered heterocyclic), wherein n is an integer ranging from 0 to 6;-   each R³⁶ and R³⁹ is independently selected from the group consisting    of H, —OH, C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, —(CH₂)_(n)(C₆-C₁₀ aryl),    —(CH₂)_(n)(5-10 membered heterocyclic), —(CH₂)_(n)O(CH₂)_(i)OR³⁷,    —(CH₂)_(n)CN(CH₂)_(n)OR³⁷, —(CH₂)_(n)CN(CH₂)_(n)R³⁷, and    —(CH₂)_(n)OR³⁷, wherein n is an integer ranging from 0 to 6 and i is    an integer ranging from 2 to 6, and the alkyl, aryl and heterocyclic    moieties of the foregoing R³⁶ and R³⁹ groups are optionally    substituted by one or more substituents independently selected from    —OH, halo, cyano, nitro, trifluoromethyl, azido, —C(O)R⁴⁰,    —C(O)OR⁴⁰, —CO(O)R⁴⁰, —OC(O)OR⁴⁰, —NR³⁷C(O)R⁴¹, —C(O)NR³⁷R⁴¹,    —NR³⁷R⁴¹, —C₁-C₆ alkyl, —(CH₂)_(n)(C₆-C₁₀ aryl), —(CH₂)_(n)(5 to 10    membered heterocyclic), —(CH₂)_(n)O(CH₂)_(i)OR³⁷, and    —(CH₂)_(n)OR³⁷, wherein n is an integer ranging from 0 to 6 and i is    an integer ranging from 2 to 6, with the proviso that when R³⁶ and    R³⁹ are both attached to the same nitrogen, then R³⁶ and R³⁹ are not    both bonded to the nitrogen directly through an oxygen;-   each R³⁷ and R⁴¹ is independently selected from the group consisting    of H, OR³⁶, C₁-C₆ alkyl and C₃-C₁₀ cycloalkyl;-   each R^(6a) and R^(6b) is independently selected from the group    consisting of hydrogen, —(CZ⁵Z⁶)_(u)—(C₃-C₆)cycloalkyl,    —(CZ⁵Z⁶)_(u)—(C₅-C₆)cycloalkenyl, —(CZ⁵Z⁶)_(u)-aryl,    —(CZ⁵Z⁶)_(u)-heteroaryl, —(CZ⁵Z⁶)_(u)-heterocycle, (C₂-C₆)alkenyl,    and (C₁-C₆)alkyl, each of which is optionally substituted with 1 to    3 independently selected Y³ groups, where u is 0, 1, 2, or 3, and    wherein when u is 2 or 3, the CZ⁵Z⁶ units may be the same or    different, or-   R^(6a) and R^(6b) taken together with adjacent atoms can form a    heterocycle;-   each Z³, Z⁴, Z⁵ and Z⁶ is independently selected from the group    consisting of H, F and (C₁-C₆)alkyl, or-   each Z³ and Z⁴, or Z⁵ and Z⁶ are selected together to form a    carbocycle, or-   two Z³ groups on adjacent carbon atoms are selected together to    optionally form a carbocycle;-   each Y² and Y³ is independently selected from the group consisting    of halogen, cyano, nitro, tetrazolyl, guanidino, amidino,    methylguanidino, azido, —C(O)Z⁷, —OC(O)NH₂, —OC(O)NHZ⁷, —OC(O)NZ⁷Z⁸,    —NHC(O)Z⁷, —NHC(O)NH₂, —NHC(O)NHZ⁷, —NHC(O)NZ⁷Z⁸, —C(O)OH, —C(O)OZ⁷,    —C(O)NH₂, —C(O)NHZ⁷, —C(O)NZ⁷Z⁸, —P(O)₃H₂, —P(O)₃(Z⁷)₂, —S(O)₃H,    —S(O)Z⁷, —S(O)₂Z⁷, —S(O)₃Z⁷, —Z⁷, —OZ⁷, —OH, —NH₂, —NHZ⁷, —NZ⁷Z⁸,    —C(═NH)NH₂, —C(═NOH)NH₂, —N-morpholino, (C₁-C₆)alkyl,    (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)haloalkyl,    (C₂-C₆)haloalkenyl, (C₂-C₆)haloalkynyl, (C₁-C₆)haloalkoxy,    —(CZ⁹Z¹⁰)_(r)NH₂, —(CZ⁹Z¹⁰)_(r)NHZ³, —(CZ⁹Z¹⁰)_(r)NZ⁷Z⁸,    —X⁶(CZ⁹Z¹⁰)_(r)—(C₃-C₈)cycloalkyl,    —X⁶(CZ⁹Z¹⁰)_(r)—(C₅-C₈)cycloalkenyl, —X⁶(CZ⁹Z¹⁰)_(r)-aryl and    —X⁶(CZ⁹Z¹⁰)_(r)-heterocycle, wherein-   r is 1, 2, 3 or 4;-   X⁶ is selected from the group consisting of O, S, NH, —C(O)—,    —C(O)NH—, —C(O)O—, —S(O)—, —S(O)₂— and —S(O)₃—;-   Z⁷ and Z⁸ are independently selected from the group consisting of an    alkyl of 1 to 12 carbon atoms, an alkenyl of 2 to 12 carbon atoms,    an alkynyl of 2 to 12 carbon atoms, a cycloalkyl of 3 to 8 carbon    atoms, a cycloalkenyl of 5 to 8 carbon atoms, an aryl of 6 to 14    carbon atoms, a heterocycle of 5 to 14 ring atoms, an aralkyl of 7    to 15 carbon atoms, and a heteroaralkyl of 5 to 14 ring atoms, or-   Z⁷ and Z⁸ together may optionally form a heterocycle;-   Z⁹ and Z¹⁰ are independently selected from the group consisting of    H, F, a (C₁-C₁₂)alkyl, a (C₆-C₁₄)aryl, a (C₅-C₁₄)heteroaryl, a    (C₇-C₁₅)aralkyl and a (C₅-C₁₄)heteroaralkyl, or-   Z⁹ and Z¹⁰ are taken together form a carbocycle, or-   two Z⁹ groups on adjacent carbon atoms are taken together to form a    carbocycle; or-   any two Y² or Y³ groups attached to adjacent carbon atoms may be    taken together to be —O[C(Z⁹)(Z¹⁰)]_(r)O or —O[C(Z⁹)(Z¹⁰)]_(r+1), or-   any two Y² or Y³ groups attached to the same or adjacent carbon    atoms may be selected together to form a carbocycle or heterocycle;    and wherein-   any of the above-mentioned substituents comprising a CH₃ (methyl),    CH₂ (methylene), or CH (methine) group which is not attached to a    halogen, SO or SO₂ group or to a N, O or S atom optionally bears on    said group a substituent selected from hydroxy, halogen,    (C₁-C₄)alkyl, (C₁-C₄)alkoxy and an —N[(C₁-C₄)alkyl][(C₁-C₄)alkyl];-   E₂ is —C≡CH or —C≡C—(CR⁴⁵R⁴⁵)_(n)R⁴⁶;-   R⁴⁵ is independently selected from the group consisting of H, a    (C₁-C₆)alkyl and a (C₃-C₈)cycloalkyl;-   R⁴⁶ is selected from the group consisting of heterocyclyl,    —N(R⁴⁷)—C(O)—N(R⁴⁷)(R⁴⁸), —N(R⁴⁷)—C(S)—N(R⁴⁷)(R⁴⁸),    —N(R⁴⁷)—C(O)—OR⁴⁸, —N(R⁴⁷)—C(O)—(CH₂)_(n)—R⁴⁸, —N(R⁴⁷)—SO₂R⁴⁷,    —(CH₂)_(n)NR⁴⁷R⁴⁸, —(CH₂)_(n)OR⁴⁸, —(CH₂)_(n)SR⁴⁹,    —(CH₂)_(n)S(O)R⁴⁹, —(CH₂)_(n)S(O)₂R⁴⁹, —OC(O)R⁴⁹, —OC(O)OR⁴⁹,    —C(O)NR⁴⁷R⁴⁸, heteroaryl optionally substituted with one or more    substituents selected from the group consisting of halo, —CF₃,    (C₁-C₆)alkoxy, —NO₂, (C₁-C₆)alkyl, —CN, —SO₂R⁵⁰ and    —(CH₂)_(n)NR⁵⁰R⁵¹, and aryl optionally substituted with one or more    substituents selected from the group consisting of halo, —CF₃,    (C₁-C₆)alkoxy, —NO₂, (C₁-C₆)alkyl, —CN, —SO₂R⁵⁰ and    —(CH₂)_(n)NR⁵⁰R⁵¹;-   R⁴⁷ and R⁴⁸ are independently selected from the group consisting of    H, (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl, heterocyclyl, —(CH₂)_(n)NR⁵⁰R⁵¹,    —(CH₂)_(n)OR⁵⁰, (CH₂)_(n)C(O)R⁴⁹, —C(O)₂R⁴⁹, —(CH₂)_(n)SR⁴⁹,    —(CH₂)_(n)S(O)R⁴⁹, —(CH₂)_(n)S(O)₂R⁴⁹, —(CH₂)_(n)R⁴⁹, —(CH₂)_(n)CN,    aryl optionally substituted with one or more substituents selected    from the group consisting of halo, —CF₃, (C₁-C₆)alkoxy, —NO₂,    (C₁-C₆)alkyl, —CN, —(CH₂)_(n)OR⁴⁹, —(CH₂)_(n)heterocyclyl,    —(CH₂)_(n)heteroaryl, —SO₂R⁵⁰ and —(CH₂)_(n)NR⁵⁰R⁵¹, and heteroaryl    optionally substituted with one or more substituents selected from    the group consisting of halo, —CF₃, (C₁-C₆)alkoxy, —NO₂,    (C₁-C₆)alkyl, —CN, —(CH₂)_(n)OR⁴⁹, —(CH₂)_(n)heterocyclyl,    —(CH₂)_(n)heteroaryl, —SO₂R⁵⁰ and —(CH₂)_(n)NR⁵⁰OR⁵¹, or-   R⁴⁷ and R⁴⁸, together with the atom to which they are attached, form    a 3-8 membered ring;-   R⁴⁹ is selected from the group consisting of (C₁-C₆)alkyl,    (C₃-C₈)cycloalkyl, heterocyclyl(C₁-C₆)alkylene, aryl(C₁-C₆)alkylene    wherein the aryl is optionally substituted with one or more    substituents selected from the group consisting of halo, —CF₃,    (C₁-C₆)alkoxy, —NO₂, (C₁-C₆)alkyl, —CN, —SO₂R⁵⁰ and    —(CH₂)_(n)NR⁵⁰R⁵¹, heteroaryl(C₁-C₆)alkylene wherein the heteroaryl    is optionally substituted with one or more substituents selected    from the group consisting of halo, —CF₃, (C₁-C₆)alkoxy, —NO₂,    (C₁-C₆)alkyl, —CN, —SO₂R⁵⁰ and —(CH₂)_(n)NR⁵⁰R⁵¹, aryl optionally    substituted with one or more substituents selected from the group    consisting of halo, —CF₃, (C₁-C₆)alkoxy, —NO₂, (C₁-C₆)alkyl, —CN,    —SO₂R⁵⁰ and —(CH₂)_(n)NR⁵⁰R⁵¹, and heteroaryl optionally substituted    with one or more substituents selected from the group consisting of    halo, —CF₃, (C₁-C₆)alkoxy, —NO₂, (C₁-C₆)alkyl, —CN, —SO₂R⁵⁰ and    —(CH₂)_(n)NR⁵⁰R⁵¹;-   R⁵⁰ and R⁵¹ are independently selected from the group consisting of    H, (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl and —C(O)R⁴⁵, or-   R⁵⁰ and R⁵¹, together with the atom to which they are attached, form    a 3-8 membered ring; and-   E³ is the group defined by —(Z¹¹)—(Z¹²)_(m)—(Z¹³)_(m1), wherein-   Z¹¹ is heterocyclyl or heterocyclylene;-   Z¹² is selected from the group consisting of OC(O), OC(S) and C(O);-   Z¹³ is selected from the group consisting of heterocyclyl, aralkyl,    N(H)R⁵², (C₁-C₃)alkyl, —OR⁵², halo, S(O)₂R⁵⁶, (C₁-C₃)hydroxyalkyl    and (C₁-C₃)haloalkyl;-   m is 0 or 1;-   m1 is 0 or 1;-   R⁵² is selected from the group consisting of H, —(CH₂)_(q)S(O)₂R⁵⁴,    R⁵⁵ NR⁵³R⁵³, (C₁-C₃alkyl), —(CH₂)_(q)OR⁵³, —C(O)R⁵⁴ and —C(O)OR⁵³;-   q is 0, 1, 2, 3 or 4;-   R⁵³ is (C₁-C₃)alkyl;-   R⁵⁴ is (C₁-C₃)alkyl or N(H)R⁵³;-   R⁵⁵ is (C₁-C₆) alkyl; and-   R⁵⁶ is selected from the group consisting of NH₂, (C₁-C₃)alkyl and    OR⁵².

In a preferred embodiment of the compounds according to the presentinvention, T is aryl or heteroaryl, wherein each of said aryl andheteroaryl is optionally substituted with 1 to 3 independently selectedR²⁰.

In a preferred embodiment of the compounds according to the presentinvention, T is selected from the group consisting of arylalkyl,cycloalkyl and heterocyclyl, wherein each of said arylalkyl, cycloalkyland heterocyclyl is optionally substituted with 1 to 3 independentlyselected R²⁰.

In a preferred embodiment of the compounds according to the presentinvention, R²⁰ is selected from the group consisting of H, halogen,—OR¹⁷ and —C(O)OR¹⁷.

In a preferred embodiment of the compounds according to the presentinvention, R²⁰ is fluorine or chloride.

In a preferred embodiment of the compounds according to the presentinvention, W is O.

In a preferred embodiment of the compounds according to the presentinvention, Z is S or O.

In a preferred embodiment of the compounds according to the presentinvention, Z is S.

In a preferred embodiment of the compounds according to the presentinvention, X and X¹ are independently selected from the group consistingof H and C₁-C₆alkyl, wherein the C₁-C₆alkyl is optionally substituted.

In a preferred embodiment of the compounds according to the presentinvention, X and X¹ are both H.

In a preferred embodiment of the compounds according to the presentinvention, X and X¹ taken together with the atom to which they areattached, form a C₃-C₇cycloalkyl.

In a preferred embodiment of the compounds according to the presentinvention, R¹, R², R³ and R⁴ are independently selected from the groupconsisting of H, halogen, trihalomethyl, OR¹⁷, —NR¹⁷R¹⁸ and C₁-C₆alkyl.

In a preferred embodiment of the compounds according to the presentinvention, R¹, R² and R⁴ are independently selected from the groupconsisting of H, halo and —OR¹⁷.

In a preferred embodiment of the compounds according to the presentinvention, R¹ is H or halogen.

In a preferred embodiment of the compounds according to the presentinvention, R¹ is halogen.

In a preferred embodiment of the compounds according to the presentinvention, R², R³ and R⁴ are each H.

In a preferred embodiment of the compounds according to the presentinvention, R¹⁷ is a C₁-C₆alkyl.

In a preferred embodiment of the compounds according to the presentinvention, R¹⁶ is H or C₁-C₆alkyl.

In a preferred embodiment of the compounds according to the presentinvention, Q is selected from the group consisting of CH₂, S,—N—(C₁-C₆alkyl), N—Y-(aryl) and —N—OMe.

In a preferred embodiment of the compounds according to the presentinvention, Q is S.

In a preferred embodiment of the compounds according to the presentinvention, Q is CH₂.

In a preferred embodiment of the compounds according to the presentinvention, Q is —N—(C₁-C₆alkyl).

In a preferred embodiment of the compounds according to the presentinvention, Q is —N—Y-(aryl).

In a preferred embodiment of the compounds according to the presentinvention, Q is —N—OMe.

In a preferred embodiment of the compounds according to the presentinvention, D is C-E.

In a preferred embodiment of the compounds according to the presentinvention, D is CH.

In a preferred embodiment of the compounds according to the presentinvention, L is C—R.

In a preferred embodiment of the compounds according to the presentinvention, R is H or halogen.

In a preferred embodiment of the compounds according to the presentinvention, L is N.

In a preferred embodiment of the compounds according to the presentinvention, E is selected from the group consisting of E¹ and E².

In a preferred embodiment of the compounds according to the presentinvention, E is E¹.

In a preferred embodiment of the compounds according to the presentinvention, E is E¹, wherein E¹ is selected from the group consisting ofH, halogen, —C(═N—OR⁴²)R⁴³, —C(O)NR⁴²R⁴³, —SO₂NR⁴²R⁴³, C(═NR⁴²)NR³⁷R⁴³,—CO₂R⁴², —C(O)(heterocyclyl), —C(O)(heteroaryl), —Y—(C₆-C₁₀ aryl),—Y-(heteroaryl), —Y-(5 to 10 membered heterocyclic), —SR^(6a),—S(O)R^(6a), —SO₂R^(6a), wherein each of said E¹ other than H andhalogen are optionally substituted with 1 to 5 independently selectedR³⁸, or E1 is (C1-C6)alkyl, which is optionally substituted with 1 to 3independently selected Y2 groups.

In a preferred embodiment of the compounds according to the presentinvention, R³⁸ is selected from the group consisting of halogen,—C(O)OR⁴⁰, —NR³⁶C(O)R³⁹, —C(O)NR³⁶R³⁹, —NR³⁶R³⁹, —OR³⁷, C₁-C₆alkyl,—C(CH₂)_(j)O(CH₂)_(i)NR³⁶R³⁹, —(CH₂)_(n)OR³⁷, —S(O)_(j)(C₁-C₆alkyl),—(CH₂)_(n)-(5 to 10 membered heterocyclic), —(CH₂)O(CH₂)_(i)(5 to 10membered heterocyclic), —(CH₂)_(n)(5 to 10 membered heteroaryl),—(CH₂)_(j)NR³⁹(CH₂)_(i)NR³⁶R³⁹, —(CH₂)_(j)NR³⁹(CH₂)_(n)R³⁶,—(CH₂)_(n)NR³⁶R³⁹, wherein j is an integer ranging from 0 to 2, n is aninteger ranging from 0 to 6, i is an integer ranging from 1 to 6, the—(CH₂)_(i)— and —(CH₂)_(n)— moieties of the foregoing R³⁸ groupsoptionally include a carbon-carbon double or triple bond where n is aninteger between 2 and 6, and the alkyl, aryl, heteroaryl, andheterocyclic moieties of the foregoing R³⁸ groups are optionallysubstituted by one or more substituents independently selected from thegroup consisting of halo, cyano, nitro, trifluoromethyl, azido, —OH,—C(O)R⁴⁰, —C(O)OR⁴⁰, —OC(O)R⁴⁰, —OC(O)OR⁴⁰, —NR³⁶C(O)R³⁹, —C(O)NR³⁶R³⁹,—(CH₂)_(n)NR³⁶R³⁹, C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, —(CH₂)_(n)(C₆-C₁₀aryl), —(CH₂)_(n)(5-10 membered heterocyclyl), —(CH₂)_(n)O(CH₂)_(i)OR³⁷,and —(CH₂)_(n)OR³⁷, wherein n is an integer ranging from 0 to 6 and i isan integer ranging from 2 to 6.

In a preferred embodiment of the compounds according to the presentinvention, the alkyl, aryl, heteroaryl, and heterocyclic moieties of theforegoing R³⁸ groups are optionally substituted by one or moresubstituents independently selected from the group consisting of —OH and—C(O)OR⁴⁰.

In a preferred embodiment of the compounds according to the presentinvention, each R⁴² and R⁴³ is independently selected from the groupconsisting of H, —Y—(C₃-C₁₀ cycloalkyl), —Y—(C₆-C₁₀ aryl), —Y—(C₆-C₁₀heteroaryl) and —Y-(5 to 10 membered heterocyclic), wherein thecycloalkyl, aryl, heteroaryl and heterocyclic moieties of the foregoingR⁴² and R⁴³ groups are optionally substituted by 1 or more substituentsindependently selected from R⁴⁴.

In a preferred embodiment of the compounds according to the presentinvention, each R⁴² and R⁴³ is independently selected from the groupconsisting of H, C₁-C₆ alkyl, C₁-C₆ heteroalkyl, —Y¹—CO₂—R³⁷ and—Y—OR³⁷.

In a preferred embodiment of the compounds according to the presentinvention, one of R⁴² and R⁴³ is H.

In a preferred embodiment of the compounds according to the presentinvention, one of R⁴² and R⁴³ is —(C₆-C₁₀ heteroaryl) or —Y-(5 to 10membered heterocyclic).

In a preferred embodiment of the compounds according to the presentinvention, Y is a bond.

In a preferred embodiment of the compounds according to the presentinvention, Y is —(C(R³⁷)(H))_(n).

In a preferred embodiment of the compounds according to the presentinvention, R⁴² and R⁴³ taken together with the nitrogen to which theyare attached form a C₅-C₉ heterocyclyl ring or a heteroaryl ring,wherein said ring is optionally substituted by 1 to 5 independentlyselected R⁴⁴ substituents, with the proviso that R⁴² and R⁴³ are notboth bonded to the nitrogen directly through an oxygen.

In a preferred embodiment of the compounds according to the presentinvention, R⁴⁴ is independently selected from the group consisting of—C(O)N³⁶R³⁹, —OR³⁷ and C₁-C₆alkyl.

In a preferred embodiment of the compounds according to the presentinvention, each R⁴⁰ is independently selected from the group consistingof H and C₁-C₁₀ alkyl.

In a preferred embodiment of the compounds according to the presentinvention, each R³⁶ and R³⁹ is independently selected from the groupconsisting of H, C₁-C₆alkyl, —(CH₂)_(n)(5 to 10 membered heterocyclic),—(CH₂)_(n)OR³⁷ and —C(O)OR⁴⁰, wherein n is an integer ranging from 0 to6 and i is an integer ranging from 2 to 6, with the proviso that whenR³⁶ and R³⁹ are both attached to the same nitrogen, then R³⁶ and R³⁹ arenot both bonded to the nitrogen directly through an oxygen.

In a preferred embodiment of the compounds according to the presentinvention, each R³⁷ and R⁴¹ is independently selected from the groupconsisting of H and C₁-C₆alkyl.

In a preferred embodiment of the compounds according to the presentinvention, R^(6a) is selected from the group consisting of—(CZ⁵Z⁶)_(u)-aryl, —(CZ⁵Z⁶))_(u)-heteroaryl and C₁-C₆alkyl, each ofwhich is optionally substituted with 1 to 3 independently selected Y³groups, wherein u is 0, 1, 2 or 3, and wherein when u is 2 or 3, theCZ⁵Z⁶ units may be the same or different.

In a preferred embodiment of the compounds according to the presentinvention, R^(6a) is selected from the group consisting of—(CZ⁵Z⁶)_(u)-aryl and —(CZ⁵Z⁶))_(u)-heteroaryl, each of which isoptionally substituted with 1 to 3 independently selected Y³ groups,wherein u is 0.

In a preferred embodiment of the compounds according to the presentinvention, Y² is —OH.

In a preferred embodiment of the compounds according to the presentinvention, Y³ is —OH.

In a preferred embodiment of the compounds according to the presentinvention, E² is —C≡C—(CR⁴⁵R⁴⁵)_(n)—R⁴⁶ wherein n is an integer rangingfrom 1 to 6.

In a preferred embodiment of the compounds according to the presentinvention, R⁴⁵ is H.

In a preferred embodiment of the compounds according to the presentinvention, R⁴⁶ is a heterocyclyl.

In a preferred embodiment of the compounds according to the presentinvention, the compounds are represented by the formula A-0:

and N-oxides, hydrates, solvates, pharmaceutically acceptable salts,prodrugs and complexes thereof, wherein

-   Z is O or S;-   X and X¹ are independently selected from the group consisting of H,    C₁-C₆ alkyl, halo, cyano and nitro, wherein C₁-C₆ alkyl is    optionally substituted;-   R¹, R², R³ and R⁴ are independently selected from the group    consisting of hydrogen, halo, trihalomethyl, —OR¹⁷, C₁-C₆ alkyl,    C₂-C₆ alkenyl or C₂-C₆ alkynyl, wherein C₁-C₆ alkyl, C₂-C₆ alkenyl    and C₂-C₆ alkynyl are optionally substituted;-   Q is O, S, NH, N(C₁-C₆ alkyl), or N—Y-(aryl);-   D is CR¹¹, or N;-   L is N, or CR, wherein R is H, halo, —CN, C₁-C₆ alkyl, C₂-C₆    alkenyl, or C₂-C₆ alkynyl, wherein C₁-C₆ alkyl, C₂-C₆ alkenyl, and    C₂-C₆ alkynyl are optionally substituted; and-   R⁷ is H, halogen, C₁-C₆ alkyl, —C(═O)NR⁹R¹⁰, —C(═O)(aryl),    —C(═O)(heterocyclyl), —C(═O)(heteroaryl), —Y-(aryl),    —Y-(heterocyclyl), —Y-(heteroaryl), —S-aryl, —S—C₁-C₆ alkyl,    —SO—C₁-C₆ alkyl, —SO₂—C₁-C₆ alkyl, —Y—NR⁹R¹⁰, —SO₂NR⁹R¹⁰ or CO₂R⁹,    wherein C₁-C₆ alkyl, aryl, heterocycle and heteroaryl are each    independently optionally substituted;-   R⁹ and R¹⁰ are independently selected from H, C₁-C₆ alkyl,    —Y-(cycloalkyl), —Y-(aryl), —Y-(heterocyclyl), —Y-(heteroaryl),    —Y—O—Y¹—O—R¹¹, —Y¹—CO₂—R¹¹, and —Y—O—R¹¹, wherein C₁-C₆ alkyl,    cycloalkyl, aryl, heterocycle, and heteroaryl are each optionally    substituted, or-   R⁹ and R¹⁰ taken together with the nitrogen to which they are    attached form a C₅-C₉ heterocyclyl ring or a heteroaryl ring,    wherein said ring is optionally substituted;-   Y is a bond or is —(C(R¹¹)(H))_(t)—, wherein t is an integer from 1    to 6;-   Y¹ is —(C(R¹¹)(H))_(t)—,-   R¹¹ at each occurrence is independently H or C₁-C₆ alkyl, wherein    C₁-C₆ alkyl is optionally substituted,-   each R²⁰ is independently selected from the group consisting of    hydrogen, halo, trihalomethyl, OR¹⁷, C₁-C₆ alkyl, C₂-C₆ alkenyl or    C₂-C₆ alkynyl, wherein C₁-C₆ alkyl, C₂-C₆ alkenyl and C₂-C₆ alkynyl    are optionally substituted, and-   each R¹⁷ is an independently selected C₁-C₆alkyl, wherein said    C₁-C₆alkyl is optionally substituted.

In a preferred embodiment of the compounds according to the presentinvention, X and X¹ are both hydrogen.

In a preferred embodiment of the compounds according to the presentinvention, R¹ is hydrogen or halogen.

In a preferred embodiment of the compounds according to the presentinvention, R¹ is fluorine.

In a preferred embodiment of the compounds according to the presentinvention, R⁴ is hydrogen or halogen.

In a preferred embodiment of the compounds according to the presentinvention, R⁴ is fluorine.

In a preferred embodiment of the compounds according to the presentinvention, R² is selected from the group consisting of H, halogen,trihalomethyl and —OR¹⁷.

In a preferred embodiment of the compounds according to the presentinvention, R³, and R²⁰ are each hydrogen.

In a preferred embodiment of the compounds according to the presentinvention, R²⁰ is —OR¹⁷.

In a preferred embodiment of the compounds according to the presentinvention, Q is S, N(C₁-C₆ alkyl), or N—Y-(aryl), more preferably S.

In a preferred embodiment of the compounds according to the presentinvention, Q is NH.

In a preferred embodiment of the compounds according to the presentinvention, D is CR¹¹, more preferably CH.

In a preferred embodiment of the compounds according to the presentinvention, L is CH or N, more preferably CH.

In a preferred embodiment of the compounds according to the presentinvention, R⁷ is H, halogen, C₁-C₆ alkyl, —C(═N—OR⁴²)R⁴³,—C(O)-heterocyclyl, Y-aryl, —CONR⁹R¹⁰, —SO₂NH₂, —SO₂NR⁹R¹⁰,—Y-heterocyclyl, —Y-heteroaryl, —S-aryl, —S—C₁-C₆ alkyl, —SO—C₁-C₆alkyl, or —SO₂—C₁-C₆ alkyl, wherein C₁-C₆ alkyl, is unsubstituted or issubstituted with one or two of hydroxy or halogen, and heterocyclyl, andheteroaryl are unsubstituted or substituted with one or two of alkoxy,alkyl, or haloalkyl.

In a preferred embodiment of the compounds according to the presentinvention, R⁷ is —CONR⁹R¹⁰.

In a preferred embodiment of the compound according to the presentinvention, R⁷ is Y-heteroaryl.

In a preferred embodiment of the compounds according to the presentinvention, R⁹ and R¹⁰ are independently H, C₁-C₆ alkyl, —Y—O—R¹¹,—Y-(heterocycle), —Y¹—CO₂—R¹¹, or —Y-(aryl), wherein C₁-C₆ alkyl isunsubstituted or is substituted with one or two of hydroxy or halogen,and heterocyclyl, and aryl are unsubstituted or are substituted with oneor two of alkoxy, alkyl, or haloalkyl.

In a preferred embodiment of the compounds according to the presentinvention, R⁹ and R¹⁰ are taken together with the nitrogen to which theyare attached to form a pyrrolidinyl, piperidinyl, piperazinyl,morpholinyl, or thiomorpholinyl ring, wherein said ring is unsubstitutedor is substituted with one or two of alkoxy, alkyl, or haloalkyl.

In a preferred embodiment of the compounds according to the presentinvention, R⁷ is H, halogen, C₁-C₆ alkyl, —SO₂NR⁹R¹⁰,—C(═O)(heterocyclyl), —Y-(heterocyclyl), or —Y-(heteroaryl), whereinC₁-C₆ alkyl is unsubstituted or is substituted with one or two ofhydroxy or halogen, and heterocyclyl, and heteroaryl are unsubstitutedor are substituted with one or two of alkoxy, alkyl, or haloalkyl.

In a preferred embodiment of the compounds according to the presentinvention, Z is sulfur.

In a preferred embodiment of the compounds according to the presentinvention, R⁷ is optionally substituted Y-heteroaryl.

In a preferred embodiment of the compounds according to the presentinvention, R⁷ is Y-heteroaryl optionally substituted on carbon with asubstituent selected from the group consisting of alkyl,-alkyl-C(O)—NR³⁶R³⁹, —(CH₂)₀₋₆heterocyclyl and —(CH₂)₀₋₂NR³⁹(CH₂)₀₋₆R³⁶,and on nitrogen with oxygen.

In a preferred embodiment of the compounds according to the presentinvention, R⁷ is selected from the group consisting of —C(═N—OR⁴²)R⁴³and —NR^(6a)R^(6b), each of which is optionally substituted.

In a preferred embodiment of the compounds according to the presentinvention, R⁷ is optionally substituted —C(O)-heterocyclyl.

In a preferred embodiment of the compounds according to the presentinvention, R⁷ is —C(O)-heterocyclyl, optionally substituted with—NR³⁶R³⁹.

In a preferred embodiment of the compounds according to the presentinvention, R⁷ is optionally substituted heterocyclyl.

In a preferred embodiment of the compounds according to the presentinvention, R⁷ is heterocyclyl optionally substituted with a substituentselected from the group consisting of alkyl and —C(O)R⁴⁰.

In a preferred embodiment of the compounds according to the presentinvention, R⁷ is optionally substituted aryl.

In a preferred embodiment of the compounds according to the presentinvention, R⁷ is aryl optionally substituted with a substituent selectedfrom the group consisting of —(CH₂)₀₋₂NR³⁹(CH₂)₀₋₆R³⁶, heterocyclyl,halogen, —S(O)₂alkyl, —C(O)NR³⁶R³⁹, —(CH₂)₀₋₆heterocyclyl, each of whichwith the exception of halogen can be optionally substituted. Preferrablythe heterocyclyl moiety is optionally substituted with alkyl or—C(O)NR³⁶R³⁹.

In a preferred embodiment of the compounds according to the presentinvention, R²⁰ is selected from the group consisting of H, halogen,alkyl, alkenyl, alkynyl and —OR¹⁷, wherein the alkyl, alkenyl, alkynyland —OR¹⁷ are optionally substituted.

In a preferred embodiment of the compounds according to the presentinvention, the compounds are represented by the formula A-1:

and N-oxides, hydrates, solvates, pharmaceutically acceptable salts,prodrugs and complexes thereof, wherein

-   R¹ is selected from the group consisting of hydrogen, halo, C₁-C₆    alkyl, C₂-C₆ alkenyl or C₂-C₆ alkynyl, wherein C₁-C₆ alkyl, C₂-C₆    alkenyl and C₂-C₆ alkynyl are optionally substituted;-   X and X¹ are independently selected from the group consisting of H    and C₁-C₆ alkyl, wherein C₁-C₆ alkyl is optionally substituted, or-   X and X¹ taken together with the atom to which they are attached,    form a C₃-C₇ cycloalkyl;-   R⁷ is H, halogen, C₁-C₆ alkyl, —C(═O)NR⁹R¹⁰, —C(═O)(aryl),    —C(═O)(heterocyclyl), —C(═O)(heteroaryl), —Y-(aryl),    —Y-(heterocyclyl), —Y-(heteroaryl), —SR^(6a), —S-aryl,    —S-(heteroaryl), —S—C₁-C₆ alkyl, —SO—C₁-C₆ alkyl, —SO₂—C₁-C₆ alkyl,    —Y—NR⁹R¹⁰, —SO₂NR⁹R¹⁰, CO₂R⁹, —C≡C—(CR⁴⁵R⁴⁵)_(n)—R⁴⁶ and    —C(═NR⁴²)NR³⁷R⁴³, wherein n is an integer ranging from 0 to 6 and    wherein C₁-C₆ alkyl, aryl, heterocycle and heteroaryl are each    independently optionally substituted with 1 to 5 independently    selected R³⁸;-   R⁹ and R¹⁰ are independently selected from H, C₁-C₆ alkyl,    —Y-(cycloalkyl), —Y—(C₁-C₆ heteroalkyl), —Y-(aryl),    —Y-(heterocyclyl), —Y-(heteroaryl), —Y—O—Y¹—O—R¹¹, —Y¹—CO₂—R¹¹,    Y—C(O)OR³⁷ and —Y—O—R¹¹, wherein said C₁-C₆ alkyl, heteroalkyl,    cycloalkyl, aryl, heterocycle, and heteroaryl are each optionally    substituted with one or more independently selected R⁴⁴, or-   R⁹ and R¹⁰ taken together with the nitrogen to which they are    attached form a C₅-C₉ heterocyclyl ring or a heteroaryl ring,    wherein said ring is optionally substituted with 1 to 5    independently selected R⁴⁴;-   each R²⁰ is independently selected from the group consisting of H,    halo, —OR¹⁷ and —C(O)OR¹⁷;-   Y is a bond or is —(C(R¹¹)(H))_(t)—, wherein t is an integer from 1    to 6;-   Y¹ is —(C(R¹¹)(H))_(t)—, and-   R¹¹ at each occurrence is independently H or C₁-C₆ alkyl, wherein    C₁-C₆ alkyl is optionally substituted.

In a preferred embodiment of the compounds according to the presentinvention, R¹ is hydrogen or halogen.

In a preferred embodiment of the compounds according to the presentinvention, R¹ is fluorine.

In a preferred embodiment of the compounds according to the presentinvention, R⁷ is selected from the group consisting of H, —C(═O)NR⁹R¹⁰,—Y-(aryl), —Y-(heteroaryl) and —S—C₁-C₆ alkyl, wherein said —Y-(aryl),—Y-(heteroaryl) and —S—C₁-C₆ alkyl are optionally substituted with 1 to5 independently selected R³⁸.

In a preferred embodiment of the compounds according to the presentinvention, R⁷ is —C(═O)NR⁹R¹⁰, optionally substituted with one or moreindependently selected R⁴⁴.

In a preferred embodiment of the compounds according to the presentinvention, R⁷ is —Y-(aryl), optionally substituted with 1 to 5independently selected R³⁸.

In a preferred embodiment of the compounds according to the presentinvention, R⁷ is —Y-(heteroaryl), optionally substituted with 1 to 5independently selected R³⁸.

In a preferred embodiment of the compounds according to the presentinvention, R³⁸ is selected from the group consisting of halogen, —OR³⁷,C₁-C₆alkyl, —(CH₂)_(n)-(5 to 10 membered heterocyclyl),—(CH₂)_(j)NR³⁹(CH₂)_(n)R³⁶, —(CH₂)_(j)NR³⁹(CH₂)_(i)NR³⁶R³⁹,—(CH₂)_(n)-heteroaryl, —C(O)NR³⁶R³⁹, —(CH₂)_(n)O(CH₂)_(i)(5 to 10membered heterocyclyl) and —(CH₂)_(j)O(CH₂)_(i)NR³⁶R³⁹, wherein n is aninteger ranging from 0 to 6, j is an integer ranging from 0 to 2, j isan integer ranging from 1 to 6 and wherein the alkyl, heteroaryl andheterocyclyl moieties of the foregoing R³⁸ groups are optionallysubstituted by one or more substituents independently selected from thegroup consisting of halo, cyano, nitro, trifluoromethyl, azido, —OH,—C(O)R⁴⁰, —C(O)OR⁴⁰, —OC(O)R⁴⁰, —OC(O)OR⁴⁰, —NR³⁶C(O)R³⁹, —C(O)NR³⁶R³⁹,—(CH₂)_(n)NR³⁶R³⁹, C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, —(CH₂)_(n)(C₆-C₁₀aryl), —(CH₂)_(n)(5-10 membered heterocyclyl), —(CH₂)_(n)O(CH₂)_(i)R³⁷,and —(CH₂)_(n)OR³⁷, wherein n is an integer ranging from 0 to 6 and i isan integer ranging from 2 to 6.

In a preferred embodiment of the compounds according to the presentinvention, R³⁸ is selected from the group consisting of —OR³⁷,C₁-C₆alkyl, —(CH₂)_(n)(5 to 10 membered heterocyclyl) and—(CH₂)_(n)O(CH₂)_(i)(5 to 10 membered heterocyclyl).

In a preferred embodiment of the compounds according to the presentinvention, R⁹ and R¹⁰ are independently selected from the groupconsisting of H, C₁-C₆ alkyl, —C₁-C₆ heteroalkyl, —Y-(aryl),—Y-(heterocyclyl), —Y-(heteroaryl), —Y—O—R¹¹ and Y—C(O)OR³⁷, wherein aC₁-C₆ alkyl, C₁-C₆ heteroalkyl, aryl, heterocyclcyl and heteroaryl areeach optionally substituted with 1 or more independently selected R⁴⁴.

In a preferred embodiment of the compounds according to the presentinvention, R⁴⁴ is selected from the group consisting of C₁-C₆ alkyl,—OR³⁷, —C(O)NR³⁶R³⁹ and —C(O)OR⁴⁶.

In a preferred embodiment of the compounds according to the presentinvention, R³⁶ is selected from the group consisting of H, C₁-C₆ alkyl,—(CH₂)_(n)OR³⁷ and —(CH₂)_(n)(heterocyclyl).

In a preferred embodiment of the compounds according to the presentinvention, R³⁹ is H or C₁-C₆ alkyl.

In a preferred embodiment of the compounds according to the presentinvention, R³⁷ is H or C₁-C₆ alkyl.

In a preferred embodiment of the compounds according to the presentinvention, R²⁰ is selected from the group consisting of H, halogen,—OR¹⁷ and —C(O)OR¹⁷.

In a preferred embodiment of the compounds according to the presentinvention, R¹⁷ is H or C₁-C₆ alkyl.

In a preferred embodiment of the compounds according to the presentinvention, R²⁰ is halogen.

In a preferred embodiment of the compounds according to the presentinvention, R²⁰ is Cl or F.

In a preferred embodiment of the compounds according to the presentinvention, R^(6a) is —(CZ⁵Z⁶)_(u)-aryl.

In a preferred embodiment of the compounds according to the presentinvention, R⁷ is selected from the group consisting of H, halogen, C₁-C₆alkyl, —CONR⁹R¹⁰, —SO₂NH₂, —SO₂NR⁹R¹⁰, —Y-heterocyclyl, —Y-heteroaryl,—S-aryl, —S—C₁-C₆ alkyl, —SO—C₁-C₆ alkyl, or —SO₂—C₁-C₆ alkyl, whereinC₁-C₆ alkyl is unsubstituted or is substituted with one or two ofhydroxy or halogen, and the heterocyclyl, and heteroaryl areunsubstituted or are substituted with one or two of alkoxy, alkyl, orhaloalkyl.

In a preferred embodiment of the compounds according to the presentinvention, R⁷ is selected from the group consisting of H, halogen, C₁-C₆alkyl, —SO₂NR⁹R¹⁰, —C(═O)(heterocyclyl), —Y-(heterocyclyl),—Y-(heteroaryl), —S-aryl, —S—C₁-C₆ alkyl, —SO—C₁-C₆ alkyl, or —SO₂—C₁-C₆alkyl, wherein C₁-C₆ alkyl is unsubstituted or is substituted with oneor two of hydroxy or halogen, and the heterocyclyl, and heteroaryl areunsubstituted or are substituted with one or two of alkoxy, alkyl, orhaloalkyl.

In a preferred embodiment of the compounds according to the presentinvention, R⁹ and R¹⁰ are independently selected from the groupconsisting of H, C₁-C₆ alkyl, C₁-C₆ heteroalkyl, —Y—O—R¹¹,—Y-(heterocycle), —Y—CO₂—R¹¹, —Y-(aryl) and —Y-(heteroaryl), whereinC₁-C₆ alkyl is unsubstituted or is substituted with one or two ofhydroxy or halogen, and the heterocyclyl, aryl and heteroaryl areunsubstituted or are substituted with one or two of alkoxy, alkyl, orhaloalkyl.

In a preferred embodiment of the compounds according to the presentinvention, R⁹ and R¹⁰ are taken together with the nitrogen to which theyare attached to form a pyrrolidinyl, piperidinyl, piperazinyl,morpholinyl, or thiomorpholinyl ring, wherein said ring is unsubstitutedor is substituted with one or two of alkoxy, alkyl, or haloalkyl.

In a preferred embodiment of the compounds according to the presentinvention, NR⁹R¹⁰ is selected from:

In a preferred embodiment of the compounds according to the presentinvention, R⁷ is unsubstituted heteroaryl.

In a preferred embodiment of the compounds according to the presentinvention, R⁷ is thiazolyl, pyridinyl, pyrimidinyl, and imidazolyl, eachof which is preferably unsubstituted or is substituted with one or twoof alkoxy, or alkyl.

In a preferred embodiment of the compounds according to the presentinvention, R⁷ is C₁-C₆ alkyl, unsubstituted or substituted with hydroxy.

In a preferred embodiment of the compounds according to the presentinvention, X and X¹ are both H.

In a preferred embodiment of the compounds according to the presentinvention, R¹⁷ is selected from the group consisting of H and C₁-C₆alkyl.

In a preferred embodiment of the compounds according to the presentinvention, R³⁸ is selected from the group consisting of —OR³⁷, C₁-C₆alkyl and —(CH₂)_(n)(5 to 10 membered heterocylic), wherein n is aninteger ranging from 0 to 6.

In a preferred embodiment of the compounds according to the presentinvention, R³⁷ is selected from the group consisting of H and C₁-C₆alkyl.

In a preferred embodiment of the compounds according to the presentinvention, the compounds are represented by the formula A-2:

and N-oxides, hydrates, solvates, pharmaceutically acceptable salts,prodrugs and complexes thereof, wherein

-   R¹ is selected from the group consisting of hydrogen, halo, C₁-C₆    alkyl, C₂-C₆ alkenyl or C₂-C₆ alkynyl, wherein C₁-C₆ alkyl, C₂-C₆    alkenyl and C₂-C₆ alkynyl are optionally substituted;-   R⁴ is selected from the group consisting of H and halogen;-   R⁷ is selected from the group consisting of H, halogen, C₁-C₆ alkyl,    —C(═O)NR⁹R¹⁰, —C(═O)(aryl), —C(═O)(heterocyclyl),    —C(═O)(heteroaryl), —Y-(aryl), —Y-(heterocyclyl), —Y-(heteroaryl),    —S-aryl, —S—C₁-C₆ alkyl, —SO—C₁-C₆ alkyl, —SO₂—C₁-C₆ alkyl,    —Y—NR⁹R¹⁰, —SO₂NR⁹R¹⁰ and CO₂R⁹, wherein C₁-C₆ alkyl, aryl,    heterocycle and heteroaryl are each independently optionally    substituted with 1 to 5 independently selected R³⁸;-   R⁹ and R¹⁰ are independently selected from the group consisting of    H, C₁-C₆ alkyl, —Y-(cycloalkyl), —Y-(aryl), —Y-(heterocyclyl),    —Y-(heteroaryl), —Y—O—Y¹—O—R¹¹, —Y¹—CO₂—R¹¹ and —Y—O—R¹¹, wherein    C₁-C₆ alkyl, cycloalkyl, aryl, heterocycle, and heteroaryl are each    optionally substituted with one or more independently selected R⁴⁴,    or-   R⁹ and R¹⁰ taken together with the nitrogen to which they are    attached form a C₅-C₉ heterocyclyl ring or a heteroaryl ring,    wherein said ring is optionally substituted;-   Y is a bond or is —(C(R¹¹)(H))_(t)—, wherein t is an integer from 1    to 6;-   Y₁ is —(C(R¹¹)(H))_(t)—, and-   R¹¹ at each occurrence is independently H or C₁-C₆ alkyl, wherein    C₁-C₆ alkyl is optionally substituted.

In a preferred embodiment of the compounds according to the presentinvention, R1 is hydrogen or halogen.

In a preferred embodiment of the compounds according to the presentinvention, R1 is fluorine.

In a preferred embodiment of the compounds according to the presentinvention, R4 is selected from the group consisting of H and halogen.

In a preferred embodiment of the compounds according to the presentinvention, R4 is fluorine.

In a preferred embodiment of the compounds according to the presentinvention, R7 is selected from the group consisting of H, halogen, C1-C6alkyl, —C(═O)NR9R10, —SO2NH2, —SO2NR9R10, —Y-heterocyclyl —Y-heteroaryl,—S-aryl, —S—C1-C6 alkyl, —SO—C1-C6 alkyl and —SO2-C1-C6 alkyl, whereinC1-C6 alkyl, heterocyclyl, heteroaryl and aryl are each optionallysubstituted with 1 to 5 independently selected R38.

In a preferred embodiment of the compounds according to the presentinvention, R7 is selected from the group consisting of H, halogen, C1-C6alkyl, —C(═O)NR9R10, —SO2NH2, —SO2NR9R10, —Y-heterocyclyl —Y-heteroaryl,—S-aryl, —S—C1-C6 alkyl, —SO—C1-C6 alkyl and —SO2-C1-C6 alkyl, whereinC1-C6 alkyl is unsubstituted or is substituted with one or two ofhydroxy or halogen, and the heterocyclyl, and heteroaryl areunsubstituted or are substituted with one or two of alkoxy, alkyl,haloalkyl or (CH2)jNR39(CH2)nO(CH2)iOR37.

In a preferred embodiment of the compounds according to the presentinvention, R7 is selected from the group consisting of H, halogen, C1-C6alkyl, —SO2NR9R10, —C(═O)(heterocyclyl), —Y-(heterocyclyl),—Y-(heteroaryl), —S-aryl, —S—C1-C6 alkyl, —SO—C1-C6 alkyl, or —SO2-C1-C6alkyl, wherein C1-C6 alkyl is unsubstituted or is substituted with oneor two of hydroxy or halogen, and the heterocyclyl, and heteroaryl areunsubstituted or are substituted with one or two of alkoxy, alkyl,haloalkyl or (CH2)jNR39(CH2)nO(CH2)iOR37.

In a preferred embodiment of the compounds according to the presentinvention, R7 is selected from the group consisting of C1-C6 alkyl,—C(═O)NR9R10, —Y-(heterocyclyl, —Y-(heteroaryl), —S—C1-C6 alkyl and—SO—C1-C6 alkyl, wherein C1-C6 alkyl is unsubstituted or is substitutedwith one or two of hydroxy or halogen, and the heterocyclyl, andheteroaryl are unsubstituted or are substituted with one or two ofalkoxy, alkyl, haloalkyl or (CH2)jNR39(CH2)nO(CH2)iOR37.

In a preferred embodiment of the compounds according to the presentinvention, R7 is CONR9R10.

In a preferred embodiment of the compounds according to the presentinvention, R9 and R10 are independently selected from the groupconsisting of H, C1-C6 alkyl, —Y—O—R11, —Y-(heterocycle), —Y1-CO2-R11and —Y-(aryl), wherein the alkyl, heterocyclyl and aryl moieties of theforegoing R9 and R10 groups are optionally substituted with 1 or moresubstituents independently selected from R44.

In a preferred embodiment of the compounds according to the presentinvention, R9 and R10 are independently selected from the groupconsisting of H, C1-C6 alkyl, —Y—O—R11, —Y-(heterocycle), —Y1-CO2-R11and —Y-(aryl), wherein C1-C6 alkyl is unsubstituted or is substitutedwith one or two of hydroxy or halogen, and the heterocyclyl, and arylare unsubstituted or are substituted with one or two of alkoxy, alkyl,haloalkyl or (CH2)jNR39(CH2)nO(CH2)iOR37.

In a preferred embodiment of the compounds according to the presentinvention, R9 and R10 taken together with the nitrogen to which they areattached form a C5-C9 heterocyclyl ring or a heteroaryl ring, whereinsaid ring is optionally substituted.

In a preferred embodiment of the compounds according to the presentinvention, R9 and R10 are taken together with the nitrogen to which theyare attached to form a pyrrolidinyl, piperidinyl, piperazinyl,morpholinyl, or thiomorpholinyl ring, wherein said ring is unsubstitutedor is substituted with one or two of alkoxy, alkyl, or haloalkyl.

In a preferred embodiment of the compounds according to the presentinvention, NR9R10 is selected from the group consisting of:

In a preferred embodiment of the compounds according to the presentinvention, the compounds are represented by the formula A-3:

and N-oxides, hydrates, solvates, pharmaceutically acceptable salts,prodrugs and complexes thereof wherein

-   R⁷ is selected from the group consisting of H, —Y-(aryl) and    —Y-(heteroaryl), wherein —Y-(aryl) and —Y-(heteroaryl) are    optionally substituted with 1 to 5 independently selected R³⁸;-   R¹ is selected from the group consisting of hydrogen, halo, C₁-C₆    alkyl, C₂-C₆ alkenyl and C₂-C₆ alkynyl, wherein C₁-C₆ alkyl, C₂-C₆    alkenyl and C₂-C₆ alkynyl are optionally substituted;-   R¹² is selected from the group consisting of H, C₁-C₆ alkyl,    —O(C₁-C₆ alkyl) and —Y-(aryl), wherein C₁-C₆ alkyl and aryl are    optionally substituted;-   Y is a bond or is —(C(R¹¹)(H))_(t)—, wherein t is an integer from 1    to 6;-   R¹¹ is H or C₁-C₆ alkyl, wherein C₁-C₆ alkyl is optionally    substituted; and-   each R₂₀ is independently selected from the group consisting of H    and halogen.

In a preferred embodiment of the compounds according to the presentinvention, R¹ is hydrogen or halogen.

In a preferred embodiment of the compounds according to the presentinvention, R¹ is fluorine.

In a preferred embodiment of the compounds according to the presentinvention, R¹² is unsubstituted C₁-C₃ alkyl or unsubstituted —Y-phenyl.

In a preferred embodiment of the compounds according to the presentinvention, R²⁰ is C1.

In a preferred embodiment of the compounds according to the presentinvention, the compounds are represented by the formula A-4:

and N-oxides, hydrates, solvates, pharmaceutically acceptable salts,prodrugs and complexes thereof, wherein

-   Z is O or S;-   X and X¹ are independently selected from the group consisting of H,    C₁-C₆ alkyl, halo, cyano and nitro, wherein C₁-C₆ alkyl is    optionally substituted;-   R¹, R², R³, R⁴, R⁵ and R⁶ are independently selected from the group    consisting of hydrogen halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆    alkynyl and NR¹⁷R¹⁸, wherein C₁-C₆ alkyl, C₂-C₆ alkenyl and C₂-C₆    alkynyl are optionally substituted;-   R¹⁷ and R¹⁸ are independently C₁-C₆alkyl;-   Q is O, S, NH, N(C₁-C₆ alkyl), or N—Y-(aryl);-   D is CR¹¹, or N;-   L is N, or CR, wherein R is selected from the group consisting of H,    halo, —CN, C₁-C₆ alkyl, C₂-C₆ alkenyl and C₂-C₆ alkynyl, wherein    C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl are optionally    substituted; and-   R¹³ is heterocyclyl or heteroaryl, wherein heterocyclyl and    heteroaryl are optionally substituted with 1 to 5 independently    selected R³⁸;-   Y is a bond or is —(C(R¹¹)(H))_(t)—, wherein t is an integer from 1    to 6; and-   R¹¹ at each occurrence is independently H or C₁-C₆ alkyl, wherein    C₁-C₆ alkyl is optionally substituted.

In a preferred embodiment of the compounds according to the presentinvention, X and X¹ are both hydrogen.

In a preferred embodiment of the compounds according to the presentinvention, R¹, R², R³ and R⁴ are independently H or halogen.

In a preferred embodiment of the compounds according to the presentinvention, R¹ is hydrogen or halogen.

In a preferred embodiment of the compounds according to the presentinvention, R¹ is fluorine or chlorine.

In a preferred embodiment of the compounds according to the presentinvention, R⁴ is hydrogen or halogen.

In a preferred embodiment of the compounds according to the presentinvention, R⁴ is fluorine or chlorine.

In a preferred embodiment of the compounds according to the presentinvention, R², R³, R⁵, and R⁶ are each hydrogen.

In a preferred embodiment of the compounds according to the presentinvention, Q is selected from the group consisting of S, N(C₁-C₆ alkyl)and N—Y-(aryl).

In a preferred embodiment of the compounds according to the presentinvention, Q is S.

In a preferred embodiment of the compounds according to the presentinvention, D is CR¹¹.

In a preferred embodiment of the compounds according to the presentinvention, R11 is H.

In a preferred embodiment of the compounds according to the presentinvention, L is CH or N.

In a preferred embodiment of the compounds according to the presentinvention, L is CH.

In a preferred embodiment of the compounds according to the presentinvention, Z is sulfur.

In a preferred embodiment of the compounds according to the presentinvention, R³⁸ is selected from C(O)OR⁴⁰ and NR³⁶R³⁹.

In a preferred embodiment of the compounds according to the presentinvention, R⁴⁰ is H or C₁-C₁₀ alkyl.

In a preferred embodiment of the compounds according to the presentinvention, R³⁶ and R³⁹ are independently C₁-C₆ alkyl.

In a preferred embodiment of the compounds according to the presentinvention, the compounds are represented by the formula A-5:

and N-oxides, hydrates, solvates, pharmaceutically acceptable salts,prodrugs and complexes thereof, wherein

-   R⁷ is selected from the group consisting of H, —C(O)NR⁴²R⁴³,    —Y-(aryl), —Y-(heteroaryl), —C(O)—(C₃-C₁₀ cycloalkyl),    —C(O)-(heterocyclyl), —C(O)—(C₆-C₁₀ aryl) and —C(O)-(heteroaryl),    wherein the aforementioned R⁷ groups other than H are optionally    substituted with 1 to 5 independently selected R³⁸;-   R⁴ is selected from the group consisting of H and halogen; and-   T is selected from the group consisting of cycloalkyl, heterocyclyl,    aryl, heteroaryl and arylalkyl, each of which is optionally    substituted with 1 to 3 independently selected R²⁰;

In a preferred embodiment of the compounds according to the presentinvention, R⁷ is selected from the group consisting of H, C(O)NR⁴²R⁴³and —Y-(heteroaryl), wherein —Y-(heteroaryl) is optionally substitutedwith 1 to 5 independently selected R³⁸;

In a preferred embodiment of the compounds according to the presentinvention, R⁷ is C(O)NR⁴²R⁴³;

In a preferred embodiment of the compounds according to the presentinvention, R⁴² and R⁴³ taken together with the nitrogen to which theyare attached form a C₅-C₉ heterocyclyl ring, wherein said ring isoptionally substituted with 1 to 5 independently selected R⁴⁴substituents, with the proviso that R⁴² and R⁴³ are not both bonded tothe nitrogen directly through and oxygen.

In a preferred embodiment of the compounds according to the presentinvention, R⁴ is halogen.

In a preferred embodiment of the compounds according to the presentinvention, R⁴ is fluorine.

In a preferred embodiment of the compounds according to the presentinvention, the compounds are represented by the formula A-6:

and N-oxides, hydrates, solvates, pharmaceutically acceptable salts,prodrugs and complexes thereof, wherein

-   R¹ is selected from the group consisting of hydrogen, halo, C₁-C₆    alkyl, C₂-C₆ alkenyl or C₂-C₆ alkynyl, wherein C₁-C₆ alkyl, C₂-C₆    alkenyl and C₂-C₆ alkynyl are optionally substituted;-   R⁷ is selected from the group consisting of H, halogen, C₁-C₆ alkyl,    —C(═O)NR⁹R¹⁰, —C(═O)(aryl), —C(═O)(heterocyclyl),    —C(═O)(heteroaryl), —Y-(aryl), —Y-(heterocyclyl), —Y-(heteroaryl),    —SR^(6a), —S-aryl, —S-(heteroaryl), —S—C₁-C₆ alkyl, —SO—C₁-C₆ alkyl,    —SO₂—C₁-C₆ alkyl, —Y—NR⁹R¹⁰, —SO₂NR⁹R¹⁰, CO₂R⁹,    —C≡C—(CR⁴⁵R⁴⁵)_(n)—R⁴⁶ and —C(═NR⁴²)NR³⁷R⁴³, wherein n is an integer    ranging from 0 to 6 and wherein C₁-C₆ alkyl, aryl, heterocycle and    heteroaryl are each independently optionally substituted with 1 to 5    independently selected R³⁸;-   R⁹ and R¹⁰ are independently selected from the group consisting of    H, C₁-C₆ alkyl, —Y-(cycloalkyl), —Y—(C₁-C₆ heteroalkyl), —Y-(aryl),    —Y-(heterocyclyl), —Y-(heteroaryl), —Y—O—Y¹—O—R¹¹, —Y¹—CO₂—R¹¹,    Y—C(O)OR³⁷ and —Y—O—R¹¹, wherein said C₁-C₆ alkyl, heteroalkyl,    cycloalkyl, aryl, heterocycle, and heteroaryl are each optionally    substituted with one or more independently selected R⁴⁴, or-   R⁹ and R¹⁰ taken together with the nitrogen to which they are    attached form a C₅-C₉ heterocyclyl ring or a heteroaryl ring,    wherein said ring is optionally substituted with 1 to 5    independently selected R⁴⁴;-   each R²⁰ is independently selected from the group consisting of H,    halo, —OR¹⁷ and —C(O)OR¹⁷;-   Y is a bond or is —(C(R¹¹)(H))_(t)—, wherein t is an integer from 1    to 6;-   Y¹ is —(C(R¹¹)(H))_(t)—; and-   R¹¹ at each occurrence is independently H or C₁-C₆ alkyl, wherein    C₁-C₆ alkyl is optionally substituted.

In a preferred embodiment of the compounds according to the presentinvention, R⁷ is selected from the group consisting of H, C(O)NR⁹R¹⁰ and—Y-(heteroaryl), wherein —Y-(heteroaryl) is optionally substituted with1 to 5 independently selected R³⁸;

In a preferred embodiment of the compounds according to the presentinvention, R⁷ is C(O)NR⁹R¹⁰;

In a preferred embodiment of the compounds according to the presentinvention, R⁹ and R¹⁰ taken together with the nitrogen to which they areattached form a C₅-C₉ heterocyclyl ring, wherein said ring is optionallysubstituted with 1 to 5 independently selected R⁴⁴ substituents.

In a preferred embodiment of the compounds according to the presentinvention, R⁷ is —Y-(heteroaryl), wherein said —Y-(heteroaryl) isoptionally substituted with 1 to 5 independently selected R³⁸.

In a preferred embodiment of the compounds according to the presentinvention, R⁷ is —Y-(heteroaryl), wherein said —Y-(heteroaryl) isoptionally substituted with one C₁-C₆ alkyl.

In a preferred embodiment of the compounds according to the presentinvention, R¹ is halogen.

In a preferred embodiment of the compounds according to the presentinvention, R¹ is fluorine.

In a preferred embodiment of the compounds according to the presentinvention, R¹⁷ is selected from the group consisting of H and C₁-C₆alkyl.

In a preferred embodiment of the compounds according to the presentinvention, R³⁸ is selected from the group consisting of —OR³⁷, C₁-C₆alkyl and —(CH₂)_(n)(5 to 10 membered heterocylic), wherein n is aninteger ranging from 0 to 6.

In a preferred embodiment of the compounds according to the presentinvention, R³⁷ is selected from the group consisting of H and C₁-C₆alkyl.

In a preferred embodiment of the compounds according to the presentinvention, each R²⁰ is independently selected from the group consistingof H, halogen and —O—(C₁-C₆)alkyl.

In a preferred embodiment of the compounds according to the presentinvention, two R²⁰ are H and the third R²⁰ is selected from the groupconsisting of H, halogen and —O—(C₁-C₆ alkyl).

In a second aspect, the invention comprises compounds of formula (B),which are inhibitors of VEGF receptor signaling and HGF receptorsignaling:

and N-oxides, hydrates, solvates, pharmaceutically acceptable salts,prodrugs and complexes thereof, wherein

-   T is selected from the group consisting of cycloalkyl, heterocyclyl,    aryl and heteroaryl, wherein each of said cycloalkyl, heterocyclyl,    aryl and heteroaryl is optionally substituted with 1 to 3 R²⁰;-   each R²⁰ is independently selected from the group consisting of —H,    halogen, trihalomethyl, —CN, —NO₂, —NH₂, —OR¹⁷, —OCF₃, —NR¹⁷R¹⁸,    —S(O)₀₋₂R¹⁷, —S(O)₂NR¹⁷R¹⁷, —C(O)OR¹⁷, —C(O)NR¹⁷R¹⁷, —N(R¹⁷)SO₂R¹⁷,    —N(R¹⁷)C(O)R¹⁷, —N(R¹⁷)C(O)R¹⁷, —C(O)R¹⁷, —C(O)SR¹⁷, C₁-C₄ alkoxy,    C₁-C₄ alkylthio, —O(CH₂)_(n)aryl, —O(CH₂)_(n)heteroaryl,    —(CH₂)₀₋₅(aryl), —(CH₂)₀₋₅(heteroaryl), C₁-C₆ alkyl, C₂-C₆ alkenyl,    C₂-C₆ alkynyl, —CH₂(CH₂)₀₋₄-T², an optionally substituted C₁₋₄    alkylcarbonyl, C₁₋₄ alkoxy, an amino optionally substituted by C₁₋₄    alkyl optionally substituted by C₁₋₄ alkoxy and a saturated or    unsaturated three- to seven-membered carboxyclic or heterocyclic    group, wherein T² is selected from the group consisting of —OH,    —OMe, —OEt, —NH₂, —NHMe, —NMe₂, —NHEt and —NEt₂, and wherein the    aryl, heteroaryl, C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl are    optionally substituted;-   W is selected from the group consisting of O, S and NH;-   Z is selected from the group consisting of O, or S and NH;-   X and X¹ are independently selected from the group consisting of H,    C₁-C₆ alkyl, halo, cyano, or nitro, wherein C₁-C₆ alkyl is    optionally substituted, or-   X and X¹ taken together with the atom to which they are attached,    form a C₃-C₇ cycloalkyl;-   R¹, R², R³ and R⁴ are independently selected from the group    consisting of hydrogen, halo, trihalomethyl, —CN, —NO₂, —NH₂, —OR¹⁷,    —NR¹⁷R¹⁸, —C(O)OR¹⁷, —C(O)R¹⁷, C₁-C₄ alkoxy, C₁-C₄ alkylthio, C₁-C₆    alkyl, C₂-C₆ alkenyl or C₂-C₆ alkynyl, wherein C₁-C₆ alkyl, C₂-C₆    alkenyl and C₂-C₆ alkynyl are optionally substituted;-   R¹⁷ is selected from the group consisting of H and R¹⁸;-   R¹⁸ is selected from the group consisting of a C₁-C₆ alkyl, an aryl,    an aryl(C₁-C₆ alkyl), a heterocyclyl and a heterocyclyl(C₁-C₆    alkyl), each of which is optionally substituted, or-   R¹⁷ and R¹⁸, taken together with a common nitrogen to which they are    attached, form an optionally substituted five- to seven-membered    heterocyclyl, the optionally substituted five- to seven-membered    heterocyclyl optionally containing at least one additional annular    heteroatom selected from the group consisting of N, O, S and P;-   R¹⁶ is selected from the group consisting of —H, —CN,    —(CH₂)₀₋₅(aryl), —(CH₂)₀₋₅(heteroaryl), C₁-C₆ alkyl, C₂-C₆ alkenyl,    C₂-C₆ alkynyl, —CH₂(CH₂)₀₋₄-T², an optionally substituted C₁₋₄    alkylcarbonyl, and a saturated or unsaturated three- to    seven-membered carboxyclic or heterocyclic group, wherein T² is    selected from the group consisting of —OH, —OMe, —OEt, —NH₂, —NHMe,    —NMe₂, —NHEt and —NEt₂, and wherein the aryl, heteroaryl, C₁-C₆    alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl are optionally substituted;-   D is selected from the group consisting of CH₂, O, S, NH, N—(C₁-C₆    alkyl), or N—Y-(aryl), —N—OMe, —NCH₂OMe and —N-Bn;-   Q is selected from the group consisting of C-E and N;-   L is N, or CR, wherein R is selected from the group consisting of    —H, halo, —CN, C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl,    wherein C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl are optionally    substituted; and-   E is selected from the group consisting of E¹, E² and E³, wherein-   E¹ is selected from the group consisting of —H, halogen, nitro,    azido, C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, —C(O)NR⁴²R⁴³, —Y—NR⁴²R⁴³,    —NR⁴²C(═O)R⁴³, —SO₂R⁴², —SO₂NR⁴²R⁴³, —NR³⁷SO₂R⁴², —NR³⁷SO₂NR⁴²R⁴³,    —C(═N—OR⁴²)R⁴³, —C(═NR⁴²)R⁴³, —NR³⁷C(═NR⁴²)R⁴³, —C(═NR⁴²)NR³⁷R⁴³,    —NR³⁷C(═NR⁴²)NR³⁷R⁴³, —C(O)R⁴², —CO₂R⁴², —C(O)(heterocyclyl),    —C(O)(C₆-C₁₀ aryl), —C(O)(heteroaryl), —Y—(C₆-C₁₀ aryl),    —Y-(heteroaryl), —Y-(5-10 membered heterocyclic), —NR^(6a)R^(6b),    —NR^(6a)SO₂R^(6b), —NR^(6a)C(O)R^(6b), —OC(O)R^(6b),    —NR^(6a)C(O)OR^(6b), —OC(O)NR^(6a)R^(6a), —OR^(6a), —SR^(6a),    —S(O)R^(6a), —SO₂R^(6a), —SO₃R^(6a), —SO₂NR^(6a)R^(6b), —SO₂NR⁴²R⁴³,    —COR^(6a), —CO₂R^(6a), —CONR^(6a)R^(6b), —(C₁-C₄)fluoroalkyl,    —(C₁-C₄)fluoroalkoxy, —(CZ³Z⁴)_(a)CN, wherein n is an integer    ranging from 0 to 6, and the aforementioned E¹ groups other than —H    and halogen are optionally substituted by 1 to 5 independently    selected R³⁸, or E¹ is selected from a moiety selected from the    group consisting of —(CZ³Z₄)_(a)-aryl, —(CZ³Z⁴)₃-heterocycle,    (C₂-C₆)alkynyl, —(CZ³Z⁴)_(n)—(C₃-C₆)cycloalkyl,    —(CZ³Z⁴)_(a)-(C₅-C₆)cycloalkenyl, (C₂-C₆) alkenyl and (C₁-C₆)alkyl,    which is optionally substituted with 1 to 3 independently selected    Y² groups, where a is 0, 1, 2, or 3, and wherein when a is 2 or 3,    the CZ³Z⁴ units may be the same or different; wherein-   each R³⁸ is independently selected from halo, cyano, nitro,    trifluoromethoxy, trifluoromethyl, azido, —C(O)R⁴⁰, —C(O)OR⁴⁰,    —OC(O)R⁴⁰, —OC(O)OR⁴⁰, —NR³⁶C(O)R³⁹, —C(O)NR³⁶R³⁹, —NR³⁶R³⁹, —OR³⁷,    —SO₂NR³⁶R³⁹, C₁-C₆ alkyl, —(CH₂)_(j)O(CH₂)_(i)NR³⁶R³⁹,    —(CH₂)_(n)O(CH₂)_(i)OR³⁷, —(CH₂)_(n)OR³⁷, —S(O)_(j)(C₁-C₆ alkyl),    —(CH₂)_(n)(C₆-C₁₀ aryl), —(CH₂)_(n)(C₅-C₁₀ heteroaryl),    —(CH₂)_(n)(5-10 membered heterocyclyl); —C(O)(CH₂)_(n)(C₆-C₁₀ aryl),    —(CH₂)_(n)O(CH₂)_(j)(C₆-C₁₀ aryl), —(CH₂)_(n)O(CH₂)_(i)(5-10    membered heterocyclyl), —C(O)(CH₂)_(n)(5-10 membered heterocyclyl),    —(CH₂)_(j)NR³⁹(CH₂)_(i)NR³⁶R³⁹, —(CH₂)_(j)NR³⁹CH₂C(O)NR³⁶R³⁹,    —(CH₂)_(j)NR³⁹(CH₂)_(i)NR³⁷C(O)R⁴⁰,    —(CH₂)_(j)NR³⁹(CH₂)_(n)O(CH₂)_(i)OR³⁷,    —(CH₂)_(j)NR³⁹(CH₂)_(i)S(O)_(j)(C₁-C₆ alkyl),    —(CH₂)_(j)NR³⁹(CH₂)_(n)R³⁶, —SO₂(CH₂)_(n)(C₆-C₁₀ aryl),    —SO₂(CH₂)_(n)(5-10 membered heterocyclyl), —(CH₂)_(n)NR³⁶R³⁹,    —NR³⁷SO₂NR³⁶R³⁹, SO₂R³⁶, C₂-C₆ alkenyl, C₃-C₁₀ cycloalkyl and C₁-C₆    alkylamino, wherein j is an integer ranging from 0 to 2, n is an    integer ranging from 0 to 6, i is an integer ranging from 0 to 6,    the —(CH₂)_(i)— and —(CH₂)_(n)— moieties of the foregoing R³⁸ groups    optionally include a carbon-carbon double or triple bond where n is    an integer between 2 and 6, and the alkyl, aryl, heteroaryl and    heterocyclyl moieties of the foregoing R³⁸ groups are optionally    substituted by one or more substituents independently selected from    halo, cyano, nitro, trifluoromethyl, azido, —OH, —C(O)R⁴⁰,    —C(O)OR⁴⁰, —OC(O)R⁴⁰, —OC(O)OR⁴⁰, —NR³⁶C(O)R³⁹, —C(O)NR³⁶R³⁹,    —(CH₂)_(n)NR³⁶R³⁹, C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, —(CH₂)_(n)(C₆-C₁₀    aryl), —(CH₂)_(n)(5-10 membered heterocyclyl),    —(CH₂)_(n)O(CH₂)_(i)OR³⁷, and —(CH₂)_(n)OR³⁷, wherein n is an    integer ranging from 0 to 6 and i is an integer ranging from 2 to 6;-   each R⁴² and R⁴³ is independently selected from the group consisting    of H, C₁-C₆ alkyl, C₁-C₆ heteroalkyl, —Y—(C₃-C₁₀ cycloalkyl),    —Y—(C₆-C₁₀ aryl), —Y—(C₆-C₁₀ heteroaryl), —Y-(5-10 membered    heterocyclic), —Y—O—Y¹—OR³⁷, —Y¹—CO₂—R³⁷, and —Y—OR³⁷, wherein the    alkyl, heteroalkyl, cycloalkyl, aryl, heteroaryl and heterocyclic    moieties of the foregoing R⁴² and R⁴³ groups are optionally    substituted by 1 or more substituents independently selected from    R⁴⁴, wherein-   Y is a bond or is —(C(R³⁷)(H))_(n),-   n is an integer ranging from 1 to 6, and-   Y¹ is —(C(R³⁷)(H))_(n), or-   R⁴² and R⁴³ taken together with the nitrogen to which they are    attached form a C₅-C₉ heterocyclyl ring or a heteroaryl ring,    wherein said ring is optionally substituted by 1 to 5 R⁴⁴    substituents, with the proviso that R⁴² and R⁴³ are not both bonded    to the nitrogen directly through an oxygen;-   each R⁴⁴ is independently selected from the group consisting of    halo, cyano, nitro, trifluoromethoxy, trifluoromethyl, azido,    —C(O)R⁴⁰, —C(O)OR⁴⁰, —OC(O)R⁴⁰, —OC(O)OR⁴⁰, —NR³⁶C(O)R³⁹,    —C(O)NR³⁶R³⁹, —NR³⁶R³⁹, —OR³⁷, —SO₂NR³⁶R³⁹, —SO₂R³⁶, —NR³⁶SO₂R³⁹,    —NR³⁶SO₂NR³⁷R⁴¹, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀    cycloalkyl, —C₁-C₆ alkylamino, —(CH₂)_(j)O(CH₂)_(i)NR³⁶R³⁹,    —(CH₂)_(n)O(CH₂)_(i)OR³⁷, —(CH₂)_(n)OR³⁷, —S(O)_(j)(C₁-C₆ alkyl),    —(CH₂)_(n)(C₆-C₁₀ aryl), —(CH₂)_(n)(5-10 membered heterocyclic),    —C(O)(CH₂)_(n)(C₆-C₁₀ aryl), —(CH₂)_(n)O(CH₂)_(j)(C₆-C₁₀ aryl),    —(CH₂)_(n)O(CH₂)_(i)(5 to 10 membered heterocyclic),    —C(O)(CH₂)_(n)(5 to 10 membered heterocyclic),    —(CH₂)_(j)NR³⁹(CH₂)_(i)NR³⁶R³⁹, —(CH₂)_(j)NR³⁹CH₂C(O)NR³⁶R³⁹,    —(CH₂)_(j)NR³⁹(CH₂)_(i)NR³⁷C(O)R⁴⁰,    —(CH₂)_(j)NR³⁹(CH₂)_(n)O(CH₂)_(i)OR³⁷,    —(CH₂)_(j)NR³⁹(CH₂)_(i)S(O)_(j)(C₁-C₆ alkyl),    —(CH₂)_(j)NR³⁹(CH₂)_(n)R³⁶, —SO₂(CH₂)_(n)(C₆-C₁₀ aryl), and    —SO₂(CH₂)_(n)(5 to 10 membered heterocyclic) wherein, j is an    integer from 0 to 2, n is an integer from 0 to 6 and i is an integer    ranging from 2 to 6, the —(CH₂)_(i)— and —(CH₂)_(n1)— moieties of    the foregoing R⁴⁴ groups optionally include a carbon-carbon double    or triple bond wherein n is an integer from 2 to 6, and the alkyl,    aryl and heterocyclic moieties of the foregoing R⁴⁴ groups are    optionally substituted by 1 or more substituents independently    selected from the group consisting of halo, cyano, nitro,    trifluoromethyl, azido, —OH, —C(O)R⁴⁰, —C(O)OR⁴⁰, —OC(O)R⁴⁰,    —OC(O)OR⁴⁰, —NR³⁶C(O)R³⁹, —C(O)NR³⁶R³⁹, —(CH₂)_(n)NR³⁶R³⁹, —SO₂R³⁶,    —SO₂NR³⁶R³⁹, C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, —(CH₂)_(n)(C₆-C₁₀    aryl), —(CH₂)_(n)(5 to 10 membered heterocyclic),    —(CH₂)_(n)O(CH₂)_(i)OR³⁷ and —(CH₂)_(n)OR³⁷, wherein n is an integer    from 0 to 6 and i is an integer from 2 to 6; and-   each R⁴⁰ is independently selected from H, C₁-C₁₀ alkyl,    —(CH₂)_(n)(C₆-C₁₀ aryl), C₃-C₁₀ cycloalkyl, and —(CH₂)_(n)(5-10    membered heterocyclic), wherein n is an integer ranging from 0 to 6;-   each R³⁶ and R³⁹ is independently selected from the group consisting    of H, —OH, C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, —(CH₂)_(n)(C₆-C₁₀ aryl),    —(CH₂)_(n)(5-10 membered heterocyclic), —(CH₂)_(n)O(CH₂)_(i)OR³⁷,    —(CH₂)_(n)CN(CH₂)_(n)OR³⁷, —(CH₂)_(n)CN(CH₂)_(n)R³⁷, and    —(CH₂)_(n)OR³⁷, wherein n is an integer ranging from 0 to 6 and i is    an integer ranging from 2 to 6, and the alkyl, aryl and heterocyclic    moieties of the foregoing R³⁶ and R³⁹ groups are optionally    substituted by one or more substituents independently selected from    —OH, halo, cyano, nitro, trifluoromethyl, azido, —C(O)R⁴⁰,    —C(O)OR⁴⁰, —CO(O)R⁴⁰, —OC(O)OR⁴⁰, —NR³⁷C(O)R⁴¹, —C(O)NR³⁷R⁴¹,    —NR³⁷R⁴¹, —C₁-C₆ alkyl, —(CH₂)_(n)(C₆-C₁₀ aryl), —(CH₂)_(n)(5 to 10    membered heterocyclic), —(CH₂)_(n)O(CH₂)_(i)OR³⁷, and    —(CH₂)_(n)OR³⁷, wherein n is an integer ranging from 0 to 6 and i is    an integer ranging from 2 to 6, with the proviso that when R³⁶ and    R³⁹ are both attached to the same nitrogen, then R³⁶ and R³⁹ are not    both bonded to the nitrogen directly through an oxygen;-   each R³⁷ and R⁴¹ is independently selected from the group consisting    of H, OR³⁶, C₁-C₆ alkyl and C₃-C₁₀ cycloalkyl;-   each R^(6a) and R^(6b) is independently selected from the group    consisting of hydrogen, —(CZ⁵Z⁶)_(u)-(C₃-C₆)cycloalkyl,    —(CZ⁵Z⁶)_(u)-(C₅-C₆)cycloalkenyl, —(CZ⁵Z⁶)_(u)-aryl,    —(CZ⁵Z⁶)_(u)-heterocycle, (C₂-C₆)alkenyl, and (C₁-C₆)alkyl, which is    optionally substituted with 1 to 3 independently selected Y³ groups,    where u is 0, 1, 2, or 3, and wherein when u is 2 or 3, the CZ⁵Z⁶    units may be the same or different, or-   R^(6a) and R^(6b) taken together with adjacent atoms can form a    heterocycle;-   each Z³, Z⁴, Z⁵ and Z⁶ is independently selected from the group    consisting of H, F and (C₁-C₆)alkyl, or-   each Z³ and Z⁴, or Z⁵ and Z⁶ are selected together to form a    carbocycle, or-   two Z³ groups on adjacent carbon atoms are selected together to    optionally form a carbocycle;-   each Y² and Y³ is independently selected from the group consisting    of halogen, cyano, nitro, tetrazolyl, guanidino, amidino,    methylguanidino, azido, —C(O)Z⁷, —OC(O)NH₂, —OC(O)NHZ⁷, —OC(O)NZ⁷Z⁸,    —NHC(O)Z⁷, —NHC(O)NH₂, —NHC(O)NHZ⁷, —NHC(O)NZ⁷Z⁸, —C(O)OH, —C(O)OZ⁷,    —C(O)NH₂, —C(O)NHZ⁷, —C(O)NZ⁷Z⁸, —P(O)₃H₂, —P(O)₃(Z⁷)₂, —S(O)₃H,    —S(O)Z⁷, —S(O)₂Z⁷, —S(O)₃Z⁷, —Z⁷, —OZ⁷, —OH, —NH₂, —NHZ⁷, —NZ⁷Z⁸,    —C(═NH)NH₂, —C(═NOH)NH₂, —N-morpholino, (C₂-C₆)alkenyl,    (C₂-C₆)alkynyl, (C₁-C₆)haloalkyl, (C₂-C₆)haloalkenyl,    (C₂-C₆)haloalkynyl, (C₁-C₆)haloalkoxy, —(CZ⁹Z¹⁰)_(r)NH₂,    —(CZ⁹Z¹⁰)_(r)NHZ³, —(CZ⁹Z¹⁰)_(r)NZ⁷Z⁸,    —X⁶(CZ⁹Z¹⁰)_(r)-(C₃-C₈)cycloalkyl,    —X⁶(CZ⁹Z¹⁰)_(r)-(C₅-C₈)cycloalkenyl, —X⁶(CZ⁹Z¹⁰)_(r)-aryl and    —X⁶(CZ⁹Z¹⁰)_(r)-heterocycle, wherein-   r is 1, 2, 3 or 4;-   X⁶ is selected from the group consisting of O, S, NH, —C(O)—,    —C(O)NH—, —C(O)O—, —S(O)—, —S(O)₂— and —S(O)₃—;-   Z⁷ and Z⁸ are independently selected from the group consisting of an    alkyl of 1 to 12 carbon atoms, an alkenyl of 2 to 12 carbon atoms,    an alkynyl of 2 to 12 carbon atoms, a cycloalkyl of 3 to 8 carbon    atoms, a cycloalkenyl of 5 to 8 carbon atoms, an aryl of 6 to 14    carbon atoms, a heterocycle of 5 to 14 ring atoms, an aralkyl of 7    to 15 carbon atoms, and a heteroaralkyl of 5 to 14 ring atoms, or-   Z⁷ and Z⁸ together may optionally form a heterocycle;-   Z⁹ and Z¹⁰ are independently selected from the group consisting of    H, F, a (C₁-C₁₂)alkyl, a (C₆-C₁₄)aryl, a (C₅-C₁₄)heteroaryl, a    (C₇-C₁₅)aralkyl and a (C₅-C₁₄)heteroaralkyl, or-   Z⁹ and Z¹⁰ are taken together form a carbocycle, or-   two Z⁹ groups on adjacent carbon atoms are taken together to form a    carbocycle; or-   any two Y² or Y³ groups attached to adjacent carbon atoms may be    taken together to be —O[C(Z⁹)(Z¹⁰)]_(r)O or —O[C(Z⁹)(Z¹⁰)]_(r+1), or-   any two Y² or Y³ groups attached to the same or adjacent carbon    atoms may be selected together to form a carbocycle or heterocycle;    and wherein-   any of the above-mentioned substituents comprising a CH₃ (methyl),    CH₂ (methylene), or CH (methine) group which is not attached to a    halogen, SO or SO₂ group or to a N, O or S atom optionally bears on    said group a substituent selected from hydroxy, halogen,    (C₁-C₄)alkyl, (C₁-C₄)alkoxy and an —N[(C₁-C₄)alkyl][(C₁-C₄)alkyl];-   E² is —C≡CH or —C≡C—(CR⁴⁵R⁴⁵)_(n)—R⁴⁶;-   R⁴⁵ is independently selected from the group consisting of H, a    (C₁-C₆)alkyl and a (C₃-C₈)cycloalkyl;-   R⁴⁶ is selected from the group consisting of heterocyclyl,    —N(R⁴⁷)—C(O)—N(R⁴⁷)(R⁴⁸), —N(R⁴⁷)—C(S)—N(R⁴⁷)(R⁴⁸),    —N(R⁴⁷)—C(O)—OR⁴⁸, —N(R⁴⁷)—C(O)—(CH₂)_(n)—R⁴⁸, —N(R⁴⁷)—SO₂R⁴⁷,    —(CH₂)_(n)NR⁴⁷R⁴⁸, —(CH₂)_(n)OR⁴⁸, —(CH₂)_(n)SR⁴⁹,    —(CH₂)_(n)S(O)R⁴⁹, —(CH₂)_(n)S(O)₂R⁴⁹, —OC(O)R⁴⁹, —OC(O)OR⁴⁹,    —C(O)NR⁴⁷R⁴⁸, heteroaryl optionally substituted with one or more    substituents selected from the group consisting of halo, —CF₃,    (C₁-C₆)alkoxy, —NO₂, (C₁-C₆)alkyl, —CN, —SO₂R⁵⁰ and    —(CH₂)_(n)NR⁵⁰R⁵¹, and aryl optionally substituted with one or more    substituents selected from the group consisting of halo, —CF₃,    (C₁-C₆)alkoxy, —NO₂, (C₁-C₆)alkyl, —CN, —SO₂R⁵⁰ and    —(CH₂)_(n)NR⁵⁰R⁵¹;-   R⁴⁷ and R⁴⁸ are independently selected from the group consisting of    H, (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl, heterocyclyl, —(CH₂)_(n)NR⁵⁰R⁵¹,    —(CH₂)_(n)OR⁵⁰, —(CH₂)_(n)C(O)R⁴⁹, —C(O)₂R⁴⁹, —(CH₂)_(n)SR⁴⁹,    —(CH₂)_(n)S(O)R⁴⁹, —(CH₂)_(n)S(O)₂R⁴⁹, —(CH₂)_(n)R⁴⁹, —(CH₂)_(n)CN,    aryl optionally substituted with one or more substituents selected    from the group consisting of halo, —CF₃, (C₁-C₆)alkoxy, —NO₂,    (C₁-C₆)alkyl, —CN, —(CH₂)_(n)OR⁴⁹, —(CH₂)_(n)heterocyclyl,    —(CH₂)_(n)heteroaryl, —SO₂R⁵⁰ and —(CH₂)_(n)NR⁵⁰R⁵¹, and heteroaryl    optionally substituted with one or more substituents selected from    the group consisting of halo, —CF₃, (C₁-C₆)alkoxy, —NO₂,    (C₁-C₆)alkyl, —CN, —(CH₂)_(n)OR⁴⁹, —(CH₂)_(n)heterocyclyl,    —(CH₂)_(n)heteroaryl, —SO₂R⁵⁰ and —(CH₂)_(n)NR⁵⁰R⁵¹, or-   R⁴⁷ and R⁴⁸, together with the atom to which they are attached, form    a 3-8 membered ring;-   R⁴⁹ is selected from the group consisting of (C₁-C₆)alkyl,    (C₃-C₈)cycloalkyl, heterocyclyl(C₁-C₆)alkylene, aryl(C₁-C₆)alkylene    wherein the aryl is optionally substituted with one or more    substituents selected from the group consisting of halo, —CF₃,    (C₁-C₆)alkoxy, —NO₂, (C₁-C₆)alkyl, —CN, —SO₂R⁵⁰ and    —(CH₂)_(n)NR⁵⁰R⁵¹, heteroaryl(C₁-C₆)alkylene wherein the heteroaryl    is optionally substituted with one or more substituents selected    from the group consisting of halo, —CF₃, (C₁-C₆)alkoxy, —NO₂,    (C₁-C₆)alkyl, —CN, —SO₂R⁵⁰ and —(CH₂)_(n)NR⁵⁰R⁵¹, aryl optionally    substituted with one or more substituents selected from the group    consisting of halo, —CF₃, (C₁-C₆)alkoxy, —NO₂, (C₁-C₆)alkyl, —CN,    —SO₂R⁵⁰ and —(CH₂)_(n)NR⁵⁰R⁵¹, and heteroaryl optionally substituted    with one or more substituents selected from the group consisting of    halo, —CF₃, (C₁-C₆)alkoxy, —NO₂, (C₁-C₆)alkyl, —CN, —SO₂R⁵⁰ and    —(CH₂)_(n)NR⁵⁰R⁵¹;-   R⁵⁰ and R⁵¹ are independently selected from the group consisting of    H, (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl and —C(O)R⁴⁵, or-   R⁵⁰ and R⁵¹, together with the atom to which they are attached, form    a 3-8 membered ring; and-   E is the group defined by —(Z¹¹)-(Z¹²)_(m)-(Z¹³)_(m1), wherein-   Z¹¹ is heterocyclyl or heterocyclylene;-   Z¹² is selected from the group consisting of OC(O), OC(S) and C(O);-   Z¹³ is selected from the group consisting of heterocyclyl, aralkyl,    N(H)R⁵², (C₁-C₃)alkyl, —OR⁵², halo, S(O)₂R⁵⁶, (C₁-C₃)hydroxyalkyl    and (C₁-C₃)haloalkyl;-   m is 0 or 1;-   m1 is 0 or 1;-   R⁵² is selected from the group consisting of H, —(CH₂)_(q)S(O)₂R⁵⁴,    R⁵⁵NR⁵³R⁵³, (C₁-C₃)alkyl, —(CH₂)_(q)OR⁵³, —C(O)R⁵⁴ and —C(O)OR⁵³;-   q is 0, 1, 2, 3 or 4;-   R⁵³ is (C₁-C₃)alkyl;-   R⁵⁴ is (C₁-C₃)alkyl or N(H)R⁵³;-   R⁵⁵ is (C₁-C₆) alkyl; and-   R⁵⁶ is selected from the group consisting of NH₂, (C₁-C₃)alkyl and    OR⁵².

In a preferred embodiment of the compounds according to the presentinvention, the compounds are represented by the formula B-0:

and N-oxides, hydrates, solvates, pharmaceutically acceptable salts,prodrugs and complexes thereof, wherein

-   Z is O or S;-   X and X¹ are independently selected from the group consisting of H,    C₁-C₆ alkyl, halo, cyano, or nitro, wherein C₁-C₆ alkyl is    optionally substituted;-   R¹, R², R³, R⁴, R⁵ and R⁶ are independently selected from the group    consisting of hydrogen, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl and C₂-C₆    alkynyl, wherein C₁-C₆ alkyl, C₂-C₆ alkenyl and C₂-C₆ alkynyl are    optionally substituted;-   Q is O, S, NH, N(C₁-C₆ alkyl), or N—Y-(aryl);-   L is N, or CR, wherein R is halo, —CN, C₁-C₆ alkyl, C₂-C₆ alkenyl,    or C₂-C₆ alkynyl, wherein C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆    alkynyl are optionally substituted; and-   R⁷ is selected from the group consisting of H, halogen, C₁-C₆ alkyl,    —C(═O)NR⁹R¹⁰, —C(═O)(aryl), —C(═O)(heterocyclyl),    —C(═O)(heteroaryl), —Y-(aryl), —Y-(heterocyclyl), —Y-(heteroaryl),    —Y—NR⁹R¹⁰, —SO₂NR⁹R¹⁰ and CO₂R⁹, wherein C₁-C₆ alkyl, aryl,    heterocyclyl and heteroaryl are each optionally substituted;-   R⁹ and R¹⁰ are independently selected from the group consisting of    H, C₁-C₆ alkyl, —Y-(cycloalkyl), —Y-(aryl), —Y-(heterocyclyl),    —Y-(heteroaryl), —Y—O—Y¹—O—R¹¹, —Y¹—CO₂—R¹¹, and —Y—O—R¹¹, wherein    C₁-C₆ alkyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl are each    optionally substituted, or-   R⁹ and R¹⁰ are taken together with the nitrogen to which they are    attached to form a C₅-C₉ heterocyclyl ring or a heteroaryl ring,    wherein said ring is optionally substituted;-   R⁸ is selected from the group consisting of H, halo and C₁-C₆ alkyl,    wherein C₁-C₆ alkyl is optionally substituted;-   Y is a bond or is —(C(R¹¹)(H))_(t)—, wherein t is an integer from I    to 6;-   Y¹ is —(C(R¹¹)(H))_(t)—, and-   R¹¹ at each occurrence is independently H or C₁-C₆ alkyl, wherein    C₁-C₆ alkyl is optionally substituted.

In a preferred embodiment of the compounds according to the presentinvention, X and X¹ are both hydrogen.

In a preferred embodiment of the compounds according to the presentinvention, R¹ is hydrogen or halogen.

In a preferred embodiment of the compounds according to the presentinvention, R¹ is fluorine.

In a preferred embodiment of the compounds according to the presentinvention, R⁴ is hydrogen or halogen.

In a preferred embodiment of the compounds according to the presentinvention, R⁴ is fluorine.

In a preferred embodiment of the compounds according to the presentinvention, R², R³, R⁵, and R⁶ are each hydrogen.

In a preferred embodiment of the compounds according to the presentinvention, Q is S, N(C₁-C₆ alkyl), or N—Y-(aryl).

In a preferred embodiment of the compounds according to the presentinvention, L is CH or N.

In a preferred embodiment of the compounds according to the presentinvention, R⁸ is selected from the group consisting of H, halo and C₁-C₆alkyl, wherein C₁-C₆ alkyl is optionally substituted with OH or NR¹⁴R¹⁵,where R¹⁴ and R¹⁵ are independently H or C₁-C₆ alkyl, or R¹⁴ and R¹⁵ aretaken together with the nitrogen to which they are attached to form aC₅-C₉ heterocyclyl ring or a heteroaryl ring, wherein said ring isoptionally substituted.

In a preferred embodiment of the compounds according to the presentinvention, R⁷ is selected from the group consisting of H, halogen, C₁-C₆alkyl, —CONR⁹R¹⁰, —SO₂NH₂, —SO₂NR⁹R¹⁰, —Y-heterocycle —Y-heteroaryl,—S-aryl, —S—C₁-C₆ alkyl, —SO—C₁-C₆ alkyl and —SO₂—C₁-C₆ alkyl, whereinC₁-C₆ alkyl is unsubstituted or is substituted with one or two ofhydroxy or halogen, and the heterocycle, and heteroaryl areunsubstituted or are substituted with one or two of alkoxy, alkyl, orhaloalkyl.

In a preferred embodiment of the compounds according to the presentinvention, R⁷ is —CONR⁹R¹⁰.

In a preferred embodiment of the compounds according to the presentinvention, R⁹ and R¹⁰ are independently selected from the groupconsisting of H, C₁-C₆ alkyl, —Y—O—R¹¹, —Y-(heterocycle), —Y¹—CO₂—R¹¹and —Y-(aryl), wherein C₁-C₆ alkyl is unsubstituted or is substitutedwith one or two of hydroxy or halogen, and the heterocycle, and aryl areunsubstituted or are substituted with one or two of alkoxy, alkyl, orhaloalkyl.

In a preferred embodiment of the compounds according to the presentinvention, R⁹ and R¹⁰ are taken together with the nitrogen to which theyare attached to form a pyrrolidinyl, piperidinyl, piperazinyl,morpholinyl, or thiomorpholinyl ring, wherein said ring is unsubstitutedor is substituted with one or two of alkoxy, alkyl, or haloalkyl.

In a preferred embodiment of the compounds according to the presentinvention, R⁷ is selected from the group consisting of H, halogen, C₁-C₆alkyl, —SO₂NR⁹R¹⁰, —C(═O)(heterocyclyl), —Y-(heterocyclyl),—Y-(heteroaryl), —S-aryl, —S—C₁-C₆ alkyl, —SO—C₁-C₆ alkyl and —SO₂—C₁-C₆alkyl, wherein C₁-C₆ alkyl is unsubstituted or is substituted with oneor two of hydroxy or halogen, and the heterocyclyl, and heteroaryl areunsubstituted or are substituted with one or two of alkoxy, alkyl, orhaloalkyl.

In a preferred embodiment of the compounds according to the presentinvention, Z is sulfur.

In a preferred embodiment of the compounds according to the presentinvention, the compounds are represented by the formula B-1:

and N-oxides, hydrates, solvates, pharmaceutically acceptable salts,prodrugs and complexes thereof, wherein

-   R¹ is selected from the group consisting of hydrogen, halo, C₁-C₆    alkyl, C₂-C₆ alkenyl and C₂-C₆ alkynyl, wherein C₁-C₆ alkyl, C₂-C₆    alkenyl and C₂-C₆ alkynyl are optionally substituted;-   R⁷ is selected from the group consisting of H, halogen, C₁-C₆ alkyl,    —C(═O)NR₉R₁₀, —C(═O)(aryl), —C(═O)(heterocyclyl),    —C(═O)(heteroaryl), —Y-(aryl), —Y-(heterocyclyl), —Y-(heteroaryl),    —Y—NR⁹R¹⁰, —SO₂NR⁹R¹⁰ and CO₂R⁹, wherein C₁-C₆ alkyl, aryl,    heterocycle and heteroaryl are each independently optionally    substituted;-   R⁹ and R¹⁰ are independently selected from the group consisting of    H, C₁-C₆ alkyl, —Y-(cycloalkyl), —Y-(aryl), —Y-(heterocyclyl),    —Y-(heteroaryl), —Y—O—Y¹—O—R¹¹, —Y¹—CO₂—R¹¹, and —Y—O—R¹¹, wherein    C₁-C₆ alkyl, cycloalkyl, aryl, heterocycle, and heteroaryl are each    optionally substituted, or-   R⁹ and R¹⁰ taken together with the nitrogen to which they are    attached form a C₅-C₉ heterocyclyl ring or a heteroaryl ring,    wherein said ring is optionally substituted;-   Y is a bond or is —(C(R¹¹)(H))_(t)—, wherein t is an integer from 1    to 6;-   Y₁ is —(C(R¹¹)(H))_(t)—;-   R¹¹ at each occurrence is independently H or C₁-C₆ alkyl, wherein    C₁-C₆ alkyl is optionally substituted; and-   R¹² is selected from the group consisting of H, C₁-C₆ alkyl and    —Y-(aryl), wherein C₁-C₆ alkyl and aryl are optionally substituted.

In a preferred embodiment of the compounds according to the presentinvention, R¹ is hydrogen or halogen.

In a preferred embodiment of the compounds according to the presentinvention, R¹ is fluorine.

In a preferred embodiment of the compounds according to the presentinvention, R¹² is unsubstituted C₁-C₃ alkyl or unsubstituted benzyl.

In a preferred embodiment of the compounds according to the presentinvention, R⁷ is —C(O)NR⁹R¹⁰.

In a preferred embodiment of the compounds according to the presentinvention, R⁷ is selected from the group consisting of

wherein the members of said group are optionally substituted by 1 to 3independently selected R³⁸.

In a preferred embodiment of the compounds according to the presentinvention, R⁷ is selected from the group consisting of

wherein the members of said group are optionally substituted with 1 to 3independently selected R³⁸.

In a third aspect, the invention provides compositions comprising acompound that is an inhibitor of kinase, or an N-oxide, hydrate,solvate, pharmaceutically acceptable salt, prodrug or complex thereof,and a pharmaceutically acceptable carrier, excipient or diluent.Preferably, the invention provides compositions comprising a compoundthat is an inhibitor of VEGF receptor signaling and HGF receptorsignaling, or an N-oxide, hydrate, solvate, pharmaceutically acceptablesalt, prodrug or complex thereof, and a pharmaceutically acceptablecarrier, excipient, or diluent. In a preferred embodiment, thecomposition further comprises an additional therapeutic agent.

In a fourth aspect, the invention provides a method of inhibitingkinase, the method comprising contacting the kinase with a compoundaccording to the present invention, or with a composition according tothe present invention. Preferably the invention provides a method ofinhibiting VEGF receptor signaling and HGF receptor signaling, themethod comprising contacting the receptor with a compound according tothe present invention, or with a composition according to the presentinvention. Inhibition of receptor protein kinase activity, preferablyVEGF and HGF receptor signaling, can be in a cell or a multicellularorganism. If in a multicellular organism, the method according to thisaspect of the invention comprises administering to the organism acompound according to the present invention, or a composition accordingto the present invention. Preferably the organism is a mammal, morepreferably a human. In a preferred embodiment, the method furthercomprises contacting the kinase with an additional therapeutic agent.

The data presented herein demonstrate the inhibitory effects of the VEGFand HGF inhibitors of the invention. These data lead one to reasonablyexpect that the compounds of the invention are useful not only forinhibition of VEGF receptor signaling and HGF receptor signaling, butalso as therapeutic agents for the treatment of proliferative diseases,including cancer and tumor growth.

Preferred compounds according to the invention include those describedin the examples below. Compounds were named using Chemdraw Ultra version6.0.2 or version 8.0.3, which are available through Cambridgesoft.com,100 Cambridge Park Drive, Cambridge, Mass. 02140, Namepro version 5.09,which is available from ACD labs, 90 Adelaide Street West, Toronto,Ontario, M5H, 3V9, Canada, or were derived therefrom.

Synthetic Schemes and Experimental Procedures

The compounds of the invention can be prepared according to the reactionschemes or the examples illustrated below utilizing methods known to oneof ordinary skill in the art. These schemes serve to exemplify someprocedures that can be used to make the compounds of the invention. Oneskilled in the art will recognize that other general syntheticprocedures may be used. The compounds of the invention can be preparedfrom starting components that are commercially available. Any kind ofsubstitutions can be made to the starting components to obtain thecompounds of the invention according to procedures that are well knownto those skilled in the art.

I. Synthesis (General Schemes)

Thieno[3,2-b]pyridine based compounds of formula A-0 may be preparedaccording to the procedures illustrated in the scheme A. Thus,thieno[3,2-b]pyridine-7-ol (I) upon treatment with POCl₃ is converted tothe chloride II. Treatment of this material with a strong base such asn-BuLi followed by an addition of carbon dioxide affords the carboxylateIII which is used without purification in the next step, providing theacyl chloride IV (presumably as a hydrochloride salt) upon its reactionwith oxalyl chloride. The acyl chloride IV is used for the next stepwithout further purification as well: upon its reaction with differentprimary and secondary amines the compound IV is converted to a varietyof primary and secondary amides V which can further be derivatized via asubstitution of the chlorine atom in the pyridine ring.

Thus, V reacting with substituted 4-nitrophenols in a high boiling pointsolvent, such as diphenyl ether in the presence of a base such aspotassium carbonate, produced the nitro derivatives VI which then arereduced to the amines VII upon treatment with a mixture NiCl₂/NaBH₄ (orother conventional reagents). The amines VII also may be used for thenext step without further purification, and upon treatment with2-phenylacetyl isothiocyanates afford phenylacetylthioureas VIII bearingthe amido-substituents such as the ones shown in the scheme A.

Substituents X and Y (up to three, same or different in each of theindicated benzene rings)are independently selected from halo, C₁-C₆alkyl, C₁-C₆ alkoxy, cyano, nitro, hydroxy, amino, C₁-C₆ alkylamino

Thieno[3,2-d]pyrimidine based compounds of formula A-0 may be preparedaccording to the procedures illustrated in the scheme B. Thus,thieno[3,2-d]pyrimidine-7-ol (IX) upon treatment with POCl₃ is convertedto the chloride X. Treatment of this material with a strong base such aslithium tetramethylpiperidide (LiTMP) generated in situ followed by anaddition of carbon dioxide affords the carboxylate XI which is usedwithout purification in the next step, providing the acyl chloride XII(presumably as a hydrochloride salt) upon its reaction with oxalylchloride. The acyl chloride XII reacting with different primary andsecondary amines is converted to a variety of primary and secondaryamides XIII which can further be derivatized via a substitution of thechlorine atom in the pyrimidine ring.

Thus, XIII reacting with substituted 4-nitrophenols in a high boilingpoint solvent, such as diphenyl ether in the presence of a base such aspotassium carbonate, produce the nitro derivatives XIV which are thenreduced to the amines XV upon treatment with a mixture NiCl₂/NaBH₄ (orother conventional reagents). The amines XV upon treatment with2-phenylacetyl isothiocyanates afford the phenylacetylthioureas XVIbearing the amido-substituents such as the ones shown in the scheme B.

Substituents X and Y (up to three, same or different in each of theindicated benzene rings) are independently selected from halo, C₁-C₆alkyl, C₁-C₆ alkoxy, cyano, nitro, hydroxy, amino, C₁-C₆ alkylamino

Thieno[3,2-b]pyridine based phenylacetylureas of formula A-0 bearingheteroaryl substituents instead of the amido moieties may be preparedaccording to the procedures illustrated in the scheme C. Thus, treatmentof the chloride II with a strong base such as n-BuLi followed by anaddition of trimethyltin (or tributyltin) chloride affords thetrimethylstannyl (or tributylstannyl) derivative XVII. This materialreacting with different heteroaryl bromides in the presence of aPd-catalyst (Stille coupling reaction or similar type reactions)produces heteroaryl-substituted thienopyridines XVIII which can furtherbe derivatized via a substitution of the chlorine atom in the pyridinering.

Substituents X and Y (up to three, same or different in each of theindicated benzene rings) are independently selected from halo, C₁-C₆alkyl, C₁-C₆ alkoxy, cyano, nitro, hydroxy, amino, C₁-C₆ alkylamino

Thus, XVIII reacting with substituted 4-nitrophenols in a high boilingpoint solvent, such as diphenyl ether in the presence of a base such aspotassium carbonate, produced the nitro derivatives XIX which are thenreduced to the amines XX upon treatment with a mixture NiCl₂/NaBH₄ (orother conventional reagents). The amines XX could be used for the nextstep without further purification, and upon treatment with2-phenylacetyl isothiocyanates afford the phenylacetylthioureas XXIbearing the heteroaryl substituents such as the ones shown in the schemeC. Heteroaryls shown in the scheme B, in turn may bear additionalsubstituents exemplified (but not limited to) alkyls, amines,alkylamino, aminoalkyls, alkoxyalkyls, hydroxyalkyls,alkylsulfonylalkyls, etc.—known in the art as solubilizingfunctionalities.

Substituents X and Y (up to three, same or different in each of theindicated benzene rings)are independently selected from halo, C₁-C₆alkyl, C₁-C₆ alkoxy, cyano, nitro, hydroxy, amino, C₁-C₆ alkylamino

Pyrrolo[2,3-d]pyrimidine based compounds of formula B-0 may be preparedaccording to the procedures illustrated in the scheme D. Treatment ofthe 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (XXII) with an alkyl halide inthe presence of a base such as sodium hydride affords the alkylatedchlorides XXIII, which reacting with substituted 4-nitrophenols in ahigh boiling point solvent, such as diphenyl ether in the presence of abase such as cesium carbonate, produced the nitro derivatives XXIVreduced to the amines XXV upon hydrogenation (or treatment withconventional reducing agents). The amines XXV reacting with2-phenylacetyl isothiocyanates afford the phenylacetylthioureas XXVIbearing the alkyl substituents such as the ones shown in the scheme D.

Substituents X and Y (up to three, same or different in each of theindicated benzene rings) are independently selected from halo,C₁-C₆alkyl, C₁-C₆alkoxy, cyano, nitro, hydroxy, amino, C₁-C₆alkylamino

Thieno[3,2-b]pyridine based phenylacetylureas of formula A-0 bearingaryl substituents may be prepared according to the proceduresillustrated in the scheme E. Thus chloride II upon lithiation andsubsequent bromination is converted to the bromide XXVII that reactingwith substituted 4-nitrophenols produces more elaborated compoundXXVIII. This material can be used for Suzuki type (and like) reactionswith a variety of aryl boronic acids (or boronates), in particular withthe ones functionalized with basic groups, thus providing compoundsXXIX. Reduction of XXIX with a mixture NiCl₂/NaBH₄ (or otherconventional reagents) affords amines XXX. The latter upon treatmentwith 2-phenylacetyl isothiocyanates afford the phenylacetylthioureasXXXI bearing aryl substituents such as the ones shown in the scheme E.

Substituents X and Y (up to three, same or different in each of theindicated benzene rings) are independently selected from halo,C₁-C₆alkyl, C₁-C₆alkoxy, cyano, nitro, hydroxy, amino, C₁-C₆alkylamino

Bromides XXVIII also can be used for Suzuki type (and like) reactionswith a variety of hydroxyphenyl boronic acids (boronates), to formphenolic compounds XXXII. These phenols reacting with different alcohols(Mitsunobu reaction), in particular functionalized with basic groups,provide compounds XXXIII. Reduction of XXXIII with a mixture NiCl₂/NaBH₄(or other conventional reagents) affords amines XXXIV which upontreatment with 2-phenylacetyl isothiocyanates afford thephenylacetylthioureas XXXV bearing the aryl substituents such as theones shown in the scheme F.

II. Specific Examples

Example 11-(4-(2-(Dimethylcarbamoyl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenyl)-3-(2-phenylacetyl)thiourea(8a) Step 1: 7-Chlorothieno[3,2-b]pyridine (2)

A stirred suspension of thieno[3,2-b]pyridin-7-ol (1, 5.0 g, 33.1 mmol)in POCl₃ (15 mL) was heated to 105° C. in an oil bath for 4 hrs. Theresultant solution was cooled to room temperature and the POCl₃ wasremoved under reduced pressure. The residue was cooled in an ice/waterbath and cold water was added. The water was made basic withconcentrated NH₄OH solution and extracted with EtOAc. The organicextract was dried over anhydrous sodium sulfate and concentrated toproduce an oil which was purified by column chromatography (eluentEtOAc-hexane, 1:4) to afford the title compound as a brown solid (4.5 g,72% yield). ¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.60 (d, J=4.9 Hz, 1H),7.80 (d, J=5.5 Hz, 1H), 7.60 (d, J=5.5 Hz, 1H), 7.30 (d, J=4.9 Hz, 1H).

Steps 2-4: 7-Chloro-N,N-dimethylthieno[3,2-b]pyridine-2-carboxamide (5)

To a stirred solution of 2 (3.0 g, 17.8 mmol) in dry THF (60 mL) at −78°C. was added n-BuLi (7.8 mL, 19.6 mmol, 2.5 M solution in hexanes) andthe resultant suspension was stirred for 15 minutes. Solid carbondioxide (excess) was added and the mixture was allowed to warm to roomtemperature over a period of 1 hour. The solvent was removed underreduced pressure and the resultant lithium carboxylate 3 was usedwithout further purification (3.88 g, quantitative).

To a stirred suspension of 3 (3.5 g, 15.9 mmol) in dry DCM (50 mL) wasadded (COCl)₂ (3.96 g, 31.2 mmol) and dry DMF (1 drop). The reactionmixture was heated to reflux for 2 hrs. The solvents were evaporated toproduce 4 (presumably as an HCl salt) which was used directly in thenext step.

Acyl chloride 4 (2.42 g, 10.5 mmol) was suspended in dry DCM (105 mL) at0° C. and Me₂NH (15.7 mL, 2M solution in THF, 31.4 mmol) was added andthe reaction mixture was stirred overnight. The solvent was removed andthe residue was dissolved in EtOAc and washed with water. The organicphase was collected and dried over anhydrous sodium sulfate thenfiltered and concentrated under reduced pressure to produce a residue,which was purified by column chromatography (eluent EtOAc-hexane, 9:1)to afford 5 as a yellow solid (1.65 g, 45% yield). ¹H NMR (400 MHz,CDCl₃) δ (ppm): 8.62 (d, J=4.8 Hz, 1H), 7.76 (s, 1H), 7.37 (d, J=4.8 Hz,1H), 3.35-3.25 (m, 3H), 3.25-3.20 (m, 3H).

Step 5:7-(2-Fluoro-4-nitrophenoxy)-N,N-dimethylthieno[3,2-b]pyridine-2-carboxamide(6)

A mixture of 5 (1.65 g, 6.85 mmol), potassium carbonate (5.68 g, 41.1mmol) and 2-fluoro-4-nitrophenol (1.65 g, 10.3 mmol) were heated to 170°C. in diphenyl ether (20 mL) for 5 hrs. The mixture was cooled to roomtemperature, diluted with EtOAc and washed with water. The organic phasewas collected, dried over anhydrous sodium sulfate and the solvents wereremoved under reduced pressure. The residue was purified by columnchromatography (eluents EtOAc-hexane 9:1, then MeOH-EtOAc 1:4) to afford6 as a yellow solid (1.02 g, 41% yield). ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 8.64 (d, J=5.3 Hz, 1H), 8.46 (dd, J=2.8 and 10.3 Hz, 1H), 8.20(ddd, J=1.3 and 2.6 and 9.0 Hz, 1H), 7.98 (s, 1H), 7.73 (dd, J=8.3 Hz,1H), 6.99 (dd, J=0.9 and 4.8 Hz, 1H), 3.25-3.30 (m, 3H), 3.02-3.11 (m,3H).

Steps 6-7:1-(4-(2-(Dimethylcarbamoyl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenyl)-3-(2-phenylacetyl)thiourea(8a)

To a solution of 6 (190 mg, 0.55 mmol) in MeOH (10 mL) at 0° C. wasadded NiCl₂×6H₂O (241 mg, 1.02 mmol) and NaBH₄ (81.4 mg, 2.2 mmol). Thereaction mixture was stirred for 1 hr, concentrated to dryness and theresultant solid was dissolved in 1 M HCl. The aqueous solution was thenmade basic with concentrated NH₄OH solution and extracted with EtOAc.The organic phase was collected, dried over anhydrous sodium sulfate andfiltered. The solvent was evaporated under reduced pressure and theresultant solid was triturated with diethyl ether to afford 7 as a whitesolid that was used immediately in the next step.

To a suspension of 7 (465.8 mg, 1.41 mmol) in THF (20 mL) was addedbenzyl isothiocyanate (374 mg, 2.12 mmol) and the reaction mixture wasstirred for 1 hr, concentrated under reduced pressure and the resultantresidue was purified by column chromatography (eluent EtOAc-MeOH 19:1)to afford a yellow solid which was triturated with Et₂O to afford 8a asan off-white solid (534 mg, 75% yield). ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 12.47 (s, 1H), 11.78 (s, 1H), 8.57 (d, J=4.2 Hz, 1H), 8.05-7.95(m, 1H), 7.93 (s, 1H), 7.52 (s, 2H), 7.33 (d, J=3.9 Hz, 1H), 7.28-7.23(m, 1H), 6.72 (d, J=5.3 Hz, 1H), 3.83 (s, 2H), 3.26 (s broad, 3H), 3.05(s broad, 3H).

Examples 2-11

Examples 2-11 (compounds 8b-k) were prepared using the same proceduresas described for the compound 8a, example 1 (scheme 1). Characterizationof 8b-k is provided in table 1.

TABLE 1

8b–k: Examples 2–11 Characterization of compounds 8b–k (examples 2–11)Cpd Ex R Name Characterization 8b 2

1-(4-(2-(2- morpholinoethylcarbamoyl) thieno[3,2- b]pyridin-7-yloxy)-3-fluorophenyl)-3-(2- phenylacetyl)thiourea ¹H NMR (400 MHz, DMSO-d₆) δppm: 12.52(s, 1H), 11.85(s, 1H), 8.96(t, J=5.3 Hz, 1H), 8.62(d, J= 5.5Hz, 1H), 8.28(s, 1H), 8.06(d, J= 10.9 Hz, 1H), 7.57(d, J=6.5 Hz, 2H),7.38–7.30(m, 5H), 6.77(d, J=5.2 Hz, 1H), 3.86(s, 2H), 3.61(t, J=4.4 Hz,4H), 3.46(q, J=6.6 Hz, 2H), 3.39– 3.36(m, 6H). 8c 3

1-(4-(2- (morpholinylcarbamoyl) thieno[3,2- b]pyridin-7-yloxy)-3-fluorophenyl)-3-(2- phenylacetyl)thiourea ¹H NMR (400 MHz, DMSO-d₆). δppm: 12.52(s, 1H), 8.72(s, 1), 8.54 (d, J=6.1 Hz, 1H), 8.0–7.98(m, 2H),7.38–7.26(m, 7H), 6.73(d, J=5.7 Hz, 1H), 3.72(s, 8H), 2.02(s, 2H). 8d 4

1-(4-(2-(3,4- dimethoxyphenylcarbamoyl) thieno[3,2-b]pyridin-7-yloxy)-3- fluorophenyl)-3-(2- phenylacetyl)thiourea ¹H NMR(400 MHz, DMSO-d₆). δ ppm: 10.64(s, 1H), 8.61(d, J=5.4 Hz, 1H), 8.51(s,1H), 8.03(d, J=12.7 Hz, 1H), 7.92(s, 1H), 7.54(m, 2H), 7.44(d, J=2.4 Hz,1H), 7.29(m, 7H), 6.96(d, J=8.8 Hz, 1H), 6.76(d, J= 6.1 Hz, 1H), 3.82(s,2H), 3.76(d, J= 8.3 Hz, 6H). 8e 5

1-(4-(2- (methylcarbamoyl) thieno[3,2-b]pyridin-7- yloxy)-3-fluorophenyl)-3-(2- phenylacetyl)thiourea ¹H NMR (400 MHz, DMSO-d₆). δppm: 12.47(s, 1H), 11.80(s, 1H), 8.92(s, 1H), 8.55(d, J=3.7 Hz, 1H),8.18(s, 1H), 8.01(d, J=11.9 Hz, 1H), 7.52(s, 2H), 7.32(s, 4H), 7.25(s,1H), 6.71(d, J=4.9 Hz, 1H), 3.81(s, 2H), 2.83(d, J=3.3 Hz, 3H). 8f 6

1-(4-(2-(3,4- dimethoxyphenethyl- carbamoyl)thieno[3,2-b]pyridin-7-yloxy)-3- fluorophenyl)-3-(2- phenylacetyl)thiourea ¹H NMR(400 MHz, DMSO-d₆). δ ppm: 12.47(s, 1H), 11.81(s, 1H), 9.03(t, J=5.7 Hz,1H), 8.56(d, J= 5.5 Hz, 1H), 8.22(s, 1H), 8.02(d, J= 11.4 Hz, 1H),7.53(s, 2H), 7.33(m, 4H), 7.27(m, 1H), 6.84(m, 2H), 6.73 (m, 2H),3.82(s, 2H), 3.70(d, J=4.5 Hz, 6H), 3.50(q, J=6.6 Hz, 2H), 2.80 (t,J=7.0 Hz,2H). 8g 7

1-(4-(2- (dieethylcarbamoyl) thieno[3,2-b]pyridin-7- yloxy)-3-fluorophenyl)-3-(2- phenylacetyl)thiourea ¹H NMR (400 MHz, DMSO-d₆). δppm: 12.58(s, 1H), 8.71(s, 1H), 8.59 (s, 1H), 8.05–7.92(m, 2H), 7.40(m,4H), 7.33(m, 3H), 6.71(s, 1H), 3.80 (s, 2H), 3.59(q, J=7.2 Hz, 4H), 1.29(m, 6H). 8h 8

1-(4-(2-(4- isopropylphenylcar- bamoyl)thieno[3,2- b]pyridin-7-yloxy)-3-fluorophenyl)-3-(2- pheenylacetyl)thiourea ¹H NMR (400 MHz, DMSO-d₆). δppm: 12.48(s, 1H), 11.81(s, 1H), 10.56(s, 1H), 8.61(d, J=5.4 Hz, 1H),8.53(s, 1H), 8.03(d, J=12.3 Hz, 2), 7.66(d, J=8.4 Hz, 2H), 7.54(m, 2H),7.33(m, 4H), 7.23(m, 3H), 6.75(d, J=5.3 Hz,, 1H), 3.82(s, 2H), 2.87(m,1H), 1.20(d, J=6.8 Hz, 6H). 8i 9

1-(4-(2- carbamoylthieno[3,2- b]pyridin-7-yloxy)-3- fluorophenyl)-3-(2-phenylacetyl)thiourea ¹H NMR (400 MHz, DMSO-d₆). δ ppm: 112.48(s, 1H),11.81(s, 1H), 8.56(dd, J=0.6 Hz and 5.5 Hz, 1H), 8.40(s, 1H), 8.25(d,J=0.8 Hz, 1H), 8.01(d, J=13.3 Hz, 1H), 7.86(s, 1H), 7.33(m, 4H), 7.25(m,1H), 6.72 (d, J=5.3 Hz, 1H), 3.82(s, 2H). 8j 10

1-(4-(2-(N-methoxy- N- meethylcarbamoyl) thieno[3,2-b]pyridin-7-yloxy)-3- fluorophenyl)-3-(2- phenylacetyl)thiourea ¹H NMR (400 MHz,DMSO-d₆). δ ppm: 12.51(s, 1H), 11.85(s, 1H), 8.63(d, J=5.3 Hz, 1H),8.22(s, 1H), 8.04(d, J=13.1 Hz, 1H), 7.57(m, 2H), 7.36(m, 4H), 7.30(m,1H), 6.77 (d, J=5.3 Hz, 1H), 3.87(s, 3H), 3.85 (s, 3H), 3.39(s, 3H). 8k11

Methyl-2-(1-(4-(2- (carbamoyl)thieno[3, 2-b]pyridin-7-yloxy)-3-fluorophenyl)-3-(2- phenylacetyl)thioureido) propanoate ¹H NMR (400MHz, DMSO-d₆). δ ppm: 12.48(s, 1H), 11.80(s, 1H), 9.28(d, J=6.9 Hz, 1H),8.59(d, J= 5.3 Hz, 1H), 8.38(s, 1H), 8.02(d, J= 12.9 Hz, 1H), 7.53(m,2H), 7.33(m, 4H), 7.28(m, 1H), 6.75(d, J=5.3 Hz, 1H), 4.49(m, 1H),3.82(s, 2H), 3.66 (s, 3H), 1.44(d, J=7.4 Hz, 3H).

Example 121-(4-(2-(Thiazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenyl)-3-(2-phenylacetyl)thiourea(13a) Step 1: 7-Chloro-2-(trimethylstannyl)thieno[3,2-b]pyridine

To a solution of 2 (1.0 g, 5.9 mmol) in dry THF (60 mL) at −78° C. wasadded n-BuLi (2.36 mL, 5.9 mmol, 2.5 M solution in hexanes) and theresultant brown precipitate was stirred for 10 min. Trimethytin chloride(1.18 g, 5.9 mmol) in dry THF (10 mL) was added slowly and the mixturewas allowed to stir at −78° C. for 2 hrs, quenched with methanol at −78°C. and the solvents were removed under reduced pressure. The residue wasdissolved in EtOAc and washed with water; the organic phase wascollected, dried over anhydrous sodium sulfate and filtered. The EtOAcwas evaporated under reduced pressure and the resultant oil was purifiedby column chromatography (eluent EtOAc-hexane 1:4) to afford 9 (1.2 g,63% yield) as a brown solid. ¹H NMR (400 MHz, CDCl₃) δ ppm: 8.21 (d,J=5.1 Hz, 1H), 7.36 (s, 1H), 6.91 (m, 1H), 0.16 (s, 9H).

Step 2: 7-Chloro-2-(thiazol-2-yl)thieno[3,2-b]pyridine (10)

To a solution of 9 (175 mg, 0.53 mmol) and 2-bromothiazole (94 mg, 0.58mmol) in dry toluene (6 mL) was added Pd(PPh₃)₄ (62 mg, 0.053 mmol) andthe reaction mixture was refluxed overnight, cooled to room temperatureand the solvents were removed under reduced pressure. The resultantsolid was triturated with hexane/Et₂O and then purified by columnchromatography (eluent EtOAc-hexane 1:1) to give 10 as a white solid (75mg, 56% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 8.65 (d, J=5.1 Hz), 8.2(s, 1H), 7.97 (s, 2H), 7.61 (d, J=5.1 Hz).

Step 3:7-(2-Fluoro-4-nitrophenoxy)-2-(thiazol-2-yl)thieno[3,2-b]pyridine (11)

To a suspension of 10 (194 mg, 0.77 mmol) in Ph₂O (10 mL) was added2-fluoro-4-nitrophenol (240 mg, 1.53 mmol) and potassium carbonate (425mg, 3.08 mmol) and the reaction mixture was heated at 180° C. for 4 hrs.The reaction mixture was cooled to room temperature and diluted withEtOAc. The resultant solution was washed with water and the organiclayer was collected, dried over anhydrous sodium sulfate and filtered.The solvents were removed under reduced pressure; the residue wasdissolved in DCM, and purified by column chromatography (eluentEtOAc-hexane 4:1) to afford 11 (190 mg, 66% yield) as a yellow solid. ¹HNMR (400 MHz, DMSO-d₆) δ ppm: 8.61 (d, J=5.5 Hz, 1H), 8.46 (dd, J=2.74and 10.37 Hz), 8.24 (s, 1H), 8.20-8.10 (m, 1H), 7.95 (s, 2H), 7.73 (t,J=8 Hz, 1H), 6.98 (d, J=5.3 Hz, 1H).

Steps 4-5.1-(4-(2-(Thiazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenyl)-3-(2-phenylacetyl)thiourea(13a)

To a suspension of 11 (190 mg, 0.55 mmol) in MeOH (10 mL) at 0° C. wasadded NiCl₂.6H₂O (241 mg, 1.02 mmol) and NaBH₄ (81.4 mg, 2.2 mmol). Thereaction mixture was allowed to stir for 1 hr, concentrated to drynessand the resultant solid was dissolved in 1 M HCl. The aqueous solutionwas then made basic with concentrated ammonium hydroxide solutionwhereupon 12 precipitated as a grey solid, which was collected byfiltration and used crude in the next step.

To a suspension of the amine 12 (152 mg, 0.44 mmol) in THF (10 mL) wasadded benzyl isothiocyanate (118 mg, 0.66 mmol) and the reaction mixturewas stirred for 1 hr, concentrated under reduced pressure and purifiedby column chromatography (eluents EtOAc-hexane 3:1, then EtOAc) toafford a yellow solid. Trituration of this material with Et₂O/hexanegave 13a (100 mg, 43% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆)δ ppm: 12.48 (s, 1H), 11.81 (s, 1H), 8.55 (d, J=5.5 Hz, 1H), 8.19 (s,1H), 8.00 (d, J=13.3 Hz, 1H), 7.95 (d, J=3.1 Hz, 1H), 7.94 (d, J=3.1 Hz,1H), 7.53 (m, 2H), 7.33 (m, 3H), 7.25 (m, 2H), 6.72 (d, J=5.5 Hz, 1H),3.82 (s, 2H).

Example 13

Examples 13-19 (compounds 13b-h) were prepared using the same proceduresas described for the compound 13a (example 12, scheme 2).Characterization of compounds 13b-h (examples 13-19) is provided intable 2.

TABLE 2

13 b–h: examples 13–19 Characterization of compounds 13b–h (examples13–19) Cpd Ex R Name Characterization 13b 13

1-(4-(2-(Pyridin-2- yl)thieno[3,2-b]pyridin-7- yloxy)-3-fluorophenyl)-3-(2-phenylacetyl)thiourea ¹H NMR (400 MHz, DMSO-d₆). δ ppm: 12.47(s, 1H),11.81(s, 1H), 8.61(d, J=2.9 Hz, 1H), 8.51 (d, J=5.5 Hz, 1H), 8.36(s,1H), 8.26(d, J=8.0 Hz, 1H), 8.0(d, J= 17 Hz, 1H), 7.93(dt, J=1.76 and7.82 Hz, 1H), 7.51(m, 2H), 7.32(m, 4H), 7.26(m, 1H), 6.65 (d, J=5.5 Hz,1H), 3.82(s, 2H). MS (m/z) 515.2 (M+H) 13c 14

N-(3-Fluoro-4-(2- (pyrimidin-2- yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothio- yl)-2-phenylacetamide ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 12.51(s, 1H), 11.82 (s, 1H), 8.95(m, 2H), 8.59(m, 1H),8.34(s, 1H), 8.04(m, 1H), 7.55(m, 3H), 7.34(m, 4H), 7.28(m, 1H), 6.75(m,1H), 3.82(s, 2H). MS (m/z) 516.2 (M+H) 13d 15

N-(3-Fluoro-4-(2-(1- methyl-1H-imidazol-2- yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothio- yl)-2-phenylacetamide ¹H NMR (400 MHz, DMSO-d₆). δ ppm: 12.48(s, 1H), 11.84 (s, 1H), 8.50(m, 1H), 8.1(s, 1H),8.04(d, J=12.1 Hz, 1H), 7.63(s, 1H), 7.56(m, 2H), 7.39 (s, 1H), 7.33(m,4H), 7.27(m, 1H), 7.19(m, 1H), 6.77(d, J= 5.7 Hz, 1H). MS (m/z) 518.2(M+H) 13e 16

N-(3-Fluoro-4-(2- (thiophen-2-yl)thieno[3,2- b]pyridin-7-yloxy)phenylcarbamothio- yl)-2-phenylacetamide ¹H NMR (400 MHz, DMSO-d₆). δ ppm: 12.48(s, 1H), 11.84 (s, 1H), 8.50(m, 1H), 8.04(m, 1H),7.79(s, 1H), 7.73(s, 1H), 7.63(m, 2H), 7.39(s, 4H), 7.27 (m, 1H),7.19(m, 1H), 6.65(m, 1H), 5.74(m, 1H), 3.81(s, 2H). MS (m/z) 520.0 (M+H)13f 17

N-(4-(2-(1,3,4- Thiadiazol-2- yl)thieno[3,2-b]pyridin-7- yloxy)-3-fluorophenylcarbamothio- yl)-2-phenylacetamide ¹H NMR (400 MHz, DMSO-d₆). δ ppm: 12.47(s, 1H), 11.82 (s, 1H), 8.57(d, J=5.5 Hz, 1H), 8.16(s,1H), 8.0(d, J=13 Hz, 1H), 7.56(m, 1H), 7.36(m, 4H), 7.26(m, 2H), 6.71(d,J= 5.3 Hz, 1H), 3.82(s, 2H). MS (m/z) 522 (M+H) 13g 18

N-(3-fluoro-4-(2-(pyridin- 3-yl)thieno[3,2-b]pyridin- 7-yloxy)phenylcarbamoythio- yl)-2-phenylacetamide ¹H NMR (400 MHz,DMSO-d₆). δ ppm: 12.49(s, 1H), 11.85(s, 1H), 9.12(dd, J=0.8 and 2.3 Hz),8.63 (dd, H=1.6 and 4,7 Hz, 1H), 8.55 (d, J=5.5 Hz, 1H), 8.27(m, 1H),8.23(s, 1H), 8.0(d, J=13.1 Hz, 1H), 7.54(m, 3H), 7.32(m, 4H), 7.26(m,2H), 6.69(dd, J=0.9 and 5.5 Hz, 1H), 3.81(s, 2H). MS (m/z) 515.2 (M+H)13h 19

N-(3-fluoro-4-(2-(2- morpholinothiazol-5- yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothio- yl)-2-phenylacetamide ¹H NMR (400 MHz,DMSO-d₆). δ ppm: 12.45(s, 1H), 11.81(s, 1H), 8.44(dd, J=1.2, 5.48 Hz,1H), 7.98(d, J=12 Hz, 1H), 7.74(s, 1H), 7.50(s, 3H), 7.33 (m, 4H),7.27(m, 2H), 6.59(d, J=5.5 Hz,, 1H), 3.82(s, 2H), 3.72(t, J=4.7 Hz, 4H),3.47(t, J=4.9 Hz, 4H). MS (m/z) 606.2 (M+H)

Example 201-(4-(2-(1-Hydroxyethyl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenyl)-3-(2-phenylacetyl)thiourea(18a) Step 1. 7-Chlorothieno[3,2-b]pyridine-2-carbaldehyde (14)

To a solution of 2 (200 mg, 1.18 mmol) in dry THF (10 mL) at −78° C. wasadded n-BuLi (0.57 mL, 1.42 mmol, 2.5 M solution in hexanes) and theresultant suspension was stirred for 20 min. Dry DMF (0.5 mL, excess)was added and the reaction mixture was stirred for an additional 2 hrs.The reaction mixture was quenched with methanol at −78° C. and water wasadded. The mixture was extracted with EtOAc and the organic extractswere combined, dried over anhydrous sodium sulfate and filtered. Thesolvent was removed under reduced pressure and the resultant yellowsolid was triturated with hexane to afford 14 (250 mg, 100% yield) as apale yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 10.2 (s, 1H), 8.78(d, J=5.1 Hz, 1H), 8.61 (s, 1H), 7.78 (d, J=5.1 Hz, 1H).

Steps 2-3.1-(7-(2-Fluoro-4-nitrophenoxy)thieno[3,2-b]pyridin-2-yl)ethanol (16)

To a solution of 14 (200 mg, 1 mmol) in dry THF (5 mL) at −78° C. wasadded methylmagnesium bromide (0.51 mL, 1 mmol, 2 M solution in dibutylether) and the reaction mixture was stirred at −78° C. for 1 hr. Thereaction was quenched with water and extracted with EtOAc. The organicphase was dried over anhydrous sodium sulfate and evaporated. Theresultant solid was washed with hexane to give 15 as a white solid (177mg, 83% yield), which was used crude in the next step.

To a suspension of 15 (170 mg, 0.79 mmol) in Ph₂O (10 mL) was added2-fluoro-4-nitrophenol (250 mg, 1.58 mmol) and potassium carbonate (436mg, 3.16 mmol) and the reaction mixture was heated at 180° C. for 4 hrs,cooled to room temperature and diluted with EtOAc. The solution waswashed with water and the organic layer was collected, dried overanhydrous sodium sulfate and filtered. The solvents were removed underreduced pressure. The residue was dissolved in DCM, and purified bycolumn chromatography (eluent EtOAc-hexane, 4:1) to afford 16 (125 mg,47% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d6) δ ppm: 8.52 (dd,J=0.8 and 5.5 Hz, 1H), 8.44 (dd, J=2.5 and 10.2 Hz, 1H), 8.15 (d, J=10.2Hz, 1H), 7.63 (t, J=8.2 Hz, 1H), 7.41 (s, 1H), 6.86 (d, J=5.3 Hz, 1H),5.96 (dd, J=0.4 Hz and 4.9 Hz), 5.09 (m, 1H), 1.49 (d, J=6.5 Hz, 3H).

Steps 4-5.1-(4-(2-(1-Hydroxyethyl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenyl)-3-(2-phenylacetyl)thiourea(18a)

To a suspension of 16 (129 mg, 0.39 mmol) in MeOH (5 mL) at 0° C. wasadded NiCl₂.6H₂O (183 mg, 0.77 mmol) and sodium borohydride (57 mg, 1.5mmol). The reaction mixture was allowed to stir for 1 hr, concentratedto dryness and the resultant solid was dissolved in 1 M HCl. The aqueoussolution was then made basic with concentrated ammonium hydroxidesolution, extracted with EtOAc and the organic extract was dried overanhydrous sodium sulfate then filtered. The solvent was removed underreduced pressure to give 17 (110 mg, 94% yield) as brown oil, which wasused immediately in the next step.

To an emulsion of 17 (110 mg, 0.36 mmol) in THF (10 mL) was added2-phenylacetyl isothiocyanate (76 mg, 0.43 mmol) and the reactionmixture was stirred for 1 hr, concentrated and the residue was purifiedby column chromatography (eluents EtOAc-hexane 3:1, then EtOAc) toafford a yellow solid which upon trituration with diethyl ether/hexanegave 18a as an off-white solid (90 mg, 52% yield). ¹H NMR (400 MHz,DMSO-d₆) δ ppm: 12.47 (s, 1H), 11.81 (s, 1H), 8.43 (d, J=5.5 Hz, 1H),8.2 (s, 1H), 7.9 (d, J=12.3 Hz, 1H), 7.51-7.44 (m, 2H), 7.30 (d, J=0.9Hz, 1H), 7.33-7.31 (m, 3H), 7.30-7.24 (m, 1H), 6.57 (d, J=5.3 Hz, 1H),5.91 (d, J=4.9 Hz, 1H), 5.09 (m, 1H), 3.9 (s, 2H), 1.49 (d, J=6.3 Hz,3H).

Example 21

1-(4-(2-(1-Hydroxy-2-methylpropyl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenyl)-3-(2-phenylacetyl)thiourea(18b)

Title compound was prepared using the same procedures as described forthe compound 18a (example 20, scheme 3). ¹H NMR (400 MHz, DMSO-d₆) δppm: 12.46 (s, 1H), 11.80 (s, 1H), 8.43 (d, J=5.9 Hz, 1H), 7.98 (d,J=2.2 Hz, 1H), 7.52-7.45 (m, 2H), 7.35 (s, 1H), 7.32 (m, 3H), 7.28 (m,1H), 6.55 (d, J=5.5 Hz, 1H), 5.91 (d, J=4.7 Hz, 1H), 4.70 (t, J=5.1 Hz,1H), 3.8 (s, 2H), 1.95 (m, 1H), 0.9 (dd, J=0.7 and 10.2 Hz, 6H).

Example 221-(4-(6-(2-Morpholinoethylcarbamoyl)thieno[3,2-d]pyrimidin-4-yloxy)-3-fluorophenyl)-3-(2-phenylacetyl)thiourea(26a) Step 1: 4-Chlorothieno[3,2-d]pyrimidine (20)

To a stirred solution of (COCl)₂ (7.33 mL, 84.11 mmol) in anhydrous(CH₂Cl)₂ (20 mL) at 0° C. under nitrogen was added DMF (4.47 mL, 57.18mmol). After 20 min a solution of thieno[3,2-d]pyrimidin-4(3H)-one (19)(4 g, 26.28 mmol) in anhydrous (CH₂Cl)₂ (5 mL) was added drop wise tothe reaction mixture which was stirred for 20 min at 0° C., warmed toroom temperature over another 20 min, heated at 80° C. for 1.5 hours,and cooled to room temperature. Finally, the reaction mixture was pouredinto water and extracted with DCM. The extract was washed sequentiallywith water, brine, dried over Na₂SO₄, filtered and evaporated to affordthe title compound 20 (4.36 g, 97% yield) as a yellow solid. ¹H NMR (400MHz, DMSO-d₆) δ(ppm): 9.02 (s, 1H), 8.59 (d, J=5.2 Hz, 1H), 7.75 (d,J=5.2 Hz, 1H).

Step 2: 4-Chlorothieno[3,2-d]pyrimidine-6-carbonyl chloride (22)

To a stirred solution of 2,2,6,6-tetramethylpiperidine (4.45 mL, 26.37mmol) in anhydrous THF (50 mL) at 0° C. under nitrogen was added n-BuLi(10.55 mL, 26.37 mmol, 2.5 M in hexanes). The reaction mixture wasstirred for 30 min, then a solution of 20 (3 g, 17.58 mmol) in anhydrousTHF (10 mL) was added drop wise at −78° C. over 30 min followed by dryice (10 g). The resultant suspension was warmed to the room temperatureover 2 hours and filtered to afford the lithium carboxylate 21 as ayellow solid (4.5 g), which was used for the next step without furtherpurification.

To a stirred solution of (COCl)₂ (2.95 mL, 33.82 mmol) in anhydrous DCM(30 mL) at 0° C. under nitrogen was added DMF (0.5 mL, 6.45 mmol). Thereaction mixture was stirred for 20 min and treated with a solution ofthe carboxylate 21 (3.71 g, 16.89 mmol) in anhydrous DCM (5 mL) (dropwise addition at 0° C.), stirred for additional 10 min and heated at 60°C. for 3 hours, cooled to room temperature and concentrated underreduced pressure to afford the title compound 22 (3.90 g, 99% yield) asa yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 9.02 (s, 1H), 8.59 (d,J=5.2 Hz, 1H), 7.75 (d, J=5.2 Hz, 1 Hz, 1H).

Step 3:4-Chloro-N-(2-morpholinoethyl)thieno[3,2-d]pyrimidine-6-carboxamide (23)

To a stirred solution of 22 (500 mg, 2.15 mmol) in anhydrous DCM (20 mL)at 0° C. under nitrogen was added 4-(2-aminoethyl)-morpholine (307 mg,2.36 mmol). The reaction mixture was allowed to warm to the roomtemperature over 3 hours and was stirred for additional 14 hours,treated with saturated aqueous solution of NHCO₃ and extracted with DCM.The organic layer was dried over Na₂SO₄, filtered, and concentrated. Theresidues was purified by flash chromatography on silica gel (eluentsMeOH-DCM, 5:95, then 1:9) to afford the title compound 23 (458 mg, 65%yield) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ(ppm): 9.13 (t, J=5.6Hz, 1H), 9.08 (s, 1H), 8.32 (s, 1H), 3.60-3.54 (m, 4H), 3.44 (q, J=6.8Hz, 2H), 2.54-2.48 (m, 2H), 2.46-2.40 (m, 4H).

Step 4:4-(2-Fluoro-4-nitrophenoxy)-N-(2-morpholinoethyl)thieno[3,2-d]pyrimidine-6-carboxamide(24)

To a stirred solution of compound 23 (458 mg, 1.40 mmol) in Ph₂O (6 mL)was added 2-fluoro-4-nitrophenol (242 mg, 1.54 mmol). The reactionmixture was heated at 120° C. for 2.5 hours, treated with K₂CO₃ (80 mg,0.56 mmol) and heated at the same temperature for additional 18 hours.After cooling, the reaction mixture was purified by flash chromatographyon a silica gel column (eluents EtOAc-hexane 5:95, 1:1, then MeOH-DCM,5:95 and 1:9), to afford the title compound 24 (570 mg, 91% yield) as ayellow solid. ¹H NMR (400 MHz, CDCl₃) δ(ppm): 9.09 (t, J=5.6 Hz, 1H),8.77 (s, 1H), 8.41 (dd, J=2.4 and 10.4 Hz, 1H), 8.30 (s, 1H), 8.22 (dd,J=2.4 and 8.8 Hz, 1H), 7.88 (t, J=8.8 Hz, 1H), 3.60-3.52 (m, 4H), 3.45(q, J=6.8 Hz, 2H), 2.50 (q, J=6.8 Hz, 2H), 2.46-2.40 (m, 4H).

Step 5:4-(4-Amino-2-fluorophenoxy)-N-(2-morpholinoethyl)thieno[3,2-d]pyrimidine-6-carboxamide(25)

To a stirred solution of 24 (1.30 g, 2.72 mmol) in anhydrous MeOH (15mL) at room temperature under nitrogen were added NiCl₂×6H₂O (605 mg,2.54 mmol) and NaBH₄ (192 mg, 5.08 mmol), respectively. The reactionmixture was stirred for 50 min, concentrated, cooled to 0° C., treatedwith HCl (10 mL, 1M) followed by addition of NH₄OH (29%) (pH 9-10), andfinally extracted with AcOEt. The organic extract was successivelywashed with water and brine, dried over Na₂SO₄, filtered, andconcentrated to afford the title compound 25 (450 mg, 85% yield) as ayellow solid. ¹H NMR (400 MHz, CDCl₃) δ(ppm): 9.04 (t, J=5.6 Hz, 1H)8.73 (s, 1H), 8.23 (s, 1H), 7.07 (t, J=8.8 Hz, 1H), 6.48 (dd, J=2.4 and13.2 Hz, 1H), 6.40 (dd, J=2.4 and 8.8 Hz, 1H), 5.47 (s, 2H), 3.62-3.52(m, 4H), 3.44 (q, J=6.8 Hz, 2H), 2.56-2.48 (m, 2H), 2.46-2.40 (m, 4H).

Step 6:1-(4-(6-(2-Morpholinoethylcarbamoyl)thieno[3,2-d]pyrimidin-4-yloxy)-3-fluorophenyl)-3-(2-phenylacetyl)thiourea(26a)

To a stirred solution of 25 (450 mg, 1.07 mmol) in anhydrous THF (10 mL)under nitrogen was slowly added benzyl isothiocyanate (0.5 mL). Thereaction mixture was stirred for 18 hours and concentrated under reducedpressure. The residue was purified by flash chromatography on a silicagel column (eluent MeOH-DCM, 5:95→10:90) followed by reversed phasechromatography purification (column Phenomene X, C18, eluent H₂O-MeOH,50:50→5:95, 10 mL/min) to afford the title compound 26a (104 mg, 16%yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ((ppm): 12.43 (s,1H), 11.80 (s, 1H), 9.07(t, J=5.6 Hz, 1H), 8.76 (s, 1H), 8.28 (s, 1H),7.93(dd, J=2.4 and 12.0 Hz, 1H), 7.54(t, J=8.8 Hz, 1H), 7.48(dd, J=1.2and 8.8 Hz, 1H), 7.39-7.30 (m, 4H), 7.30-7.20 (m, 1H), 3.82 (s, 2H),3.60-3.54 (m, 4H), 3.45(q, J=6.4 Hz, 2H), 2.50 (m, 2H), 2.48-2.40 (m,4H).

Examples 23-27

Examples 23-27 (compounds 26b-e) were prepared using the same proceduresas described for the compound 26a, example 22 (scheme 4).Characterization of compounds 26b-e (examples 23-27) is provided intable 3.

TABLE 3

26 b–e: Examples 23–27 Characterization of compounds 26b–e (examples23–27) Cpd Ex R Name Characterization 26b 23

1-(4-(6- (Dimethylcarbamoyl) thieno[3,2-d]pyrimidin- 4-yloxy)-3-fluorophenyl)-3-(2- phenylacetyl)thiourea ¹H NMR (400 MHz,, DMSO-d₆) δ(ppm): 8.77(s, 1H), 8.01(s, 1H), 7.93(dd, J=2.4 znd 12.4 Hz, 1H),7.54(t, J=8.4 Hz, 1H), 7.50–7.44 (m, 1H), 7.38–7.30(m, 4H), 7.30–7.23(m, 1H), 3.82(s, 2H), 3.24(s, 3H), 3.07(s, 3H). 26c 24

1-(4-(6-(4-N- Methylpiperazylcarbam- oyl)thieno[3,2-d]pyrimidin-4-yloxy)- 3-fluorophenyl)-3-(2- phenylacetyl)thiourea ¹H NMR(400 Hz, DMSO-d₆) δ (ppm): 12.43(s, 1H), 11.80(s, 1H), 8.77(s, 1H),7.93(s, 1H), 7.93(dd, J=2.0 and 12.0 Hz, 1H), 7.53(t, J=8.4 Hz, 1H),7.48(dd, J= 2.0 and 8.4 Hz, 1H), 7.38–7.30 (m, 4H), 7.30–7.224(m, 1H),3.82 (s, 2H), 3.74–3.62(m, 4H), 2.48– 2.36(m, 4H), 2.25(bs, 3H). 26d 25

1-(4-(6- (Methylcarbamoyl) thieno[3,2-d]pyrimidin-4- yloxy)-3-fluorophenyl)-3-(2- phenylacetyl)thiourea ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 12.42(s, 1H), 11.80(s, 1H), 9.10(q, J=4.4 Hz, 1H), 8.76 (s, 1H),8.23(s, 1H), 7.92(dd, J= 2.0 and 12.0 Hz, 1H), 7.54(t, J= 8.8 Hz, 1H),7.48(dd, 2.0 and 8.8 Hz, 1H), 7.36–7.30(m, 4H), 7.30– 7.24(m, 1H),3.82(s, 2H), 2.87(d, J=4.4 Hz, 1H). 26e 26

1-(4-(6-(N-Methoxy-N- methylcarbamoyl) thieno[3,2-d]pyrimidin-4-yloxy)-3- fluorophenyl)-3-(2- phenylacetyl)thiourea ¹H NMR (400 MHz,DMSO-d₆) δ (ppm): 8.79(s, 1H), 8.23(s, 1H), 7.93(dd, J=2.0 and 11.6 Hz,1H), 7.55(t, J=8.8 Hz, 1H), 7.48(dd, J= 2.0 and 8.8 Hz, 1H), 7.36–7.30(m, 4H), 7.30–7.24(m, 1H), 3.87 (s, 3H), 3.82(s, 2H), 3.39(s, 3H). 26f27

1-(4-(6- Carbamoylthieno[3,2- d]pyrimidin-4-yloxy)-3-fluorophenyl)-3-(2- phenylacetyl)thiourea ¹ H NMR (400 MHz, DMSO-d₆) δ(ppm): 12.43(s, 1H), 11.80(s, 1H), 8.76(s, 1H), 8.55(bs, 1H), 8.29(s,1H), 8.07(bs, 1H), 7.93 (dd, J=2.0 and 12 Hz, 1H), 7.54 (t, J=8.8 Hz,1H), 7.48(dd, J= 2.0 and 8.8 Hz, 1H), 7.36–7.30(m, 4H), 7.30–7.23(m,1H), 3.82(s, 2H).

Example 281-(4-(5-Methyl-5H-pyrrolo[3,2-d]pyrimidin-4-yloxy)-3-fluorophenyl)-3-(2-phenylacetyl)thiourea(31a) Step 1: 4-Chloro-5-methyl-5H-pyrrolo[3,2-d]pyrimidine (28)

To a stirred solution of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (27) (J.Org. Chem., 2001, 66, 17, 5723-5730) (643 mg, 4.15 mmol) in DMF (41 mL)was added NaH (60% in mineral oil, 330 mg, 8.3 mmol) in one portion at0° C. and the mixture was stirred for 1 h followed by addition of methyliodide (0.28 mL, 4.5 mmol). The reaction mixture was allowed to warm upto the room temperature, stirred for an additional hour and quenchedwith AcOH (1 mL) to form a suspension which was stirred for 10 min andconcentrated under reduced pressure to give a solid. This material wasdissolved in AcOEt, the solution was washed with cold saturated NaHCO₃solution and water, dried over Na₂SO₄, and concentrated to produce thetitle compound 28 as a pale yellow solid (640 mg, 93% yield). ¹H NMR(400 MHz, CD₃OD) δ(ppm): 8.51 (s, 1H), 7.75 (d, J=3.3 Hz, 1H), 6.62 (d,J=3.3 Hz, 2H), 4.15 (s, 1H). LRMS (M+1) 168.1 (100%), 170.1 (34%).

Step 2: 4-(2-Fluoro-4-nitrophenoxy)-5-methyl-5H-pyrrolo[3,2-d]pyrimidine(29)

A suspension of 4-chloro-5-methyl-5H-pyrrolo[3,2-d]pyrimidine (28) (300mg, 1.79 mmol), 4-nitro-2-fluorophenol (422 mg, 2.69 mmol) and cesiumcarbonate (1.2 g, 3.58 mmol) in diphenyl ether (18 mL) was stirredovernight at 140° C. The reaction mixture was cooled to roomtemperature, concentrated under reduced pressure and the residue wastriturated with Et₂O, filtered, and dried to afford the title compound29 as a grey solid (258 mg, 49% yield). LRMS (M+1) 289.1 (100%).

Step 3:4-(5-Methyl-5H-pyrrolo[3,2-d]pyrimidin-4-yloxy)-3-fluorobenzenamine (30)

To a solution of4-(2-fluoro-4-nitrophenoxy)-5-methyl-5H-pyrrolo[3,2-d]pyrimidine (29)(253.6 mg, 0.879 mmol) in AcOH (3 mL) at 90° C. was added iron powder(245 mg, 4.4 mmol). The mixture was stirred vigorously for 10 min andfiltered. The filtrate was concentrated under reduced pressure toproduce a solid, which was dissolved in DCM. The resultant solution waswashed with cold NaHCO₃ solution and water, dried over Na₂SO₄ andconcentrated to provide a residue which was purified by columnchromatography (eluent MeOH—CH₂Cl₂ 1:20) to afford the title compound 30as a brown solid (120.6 mg, 53% yield). LRMS (M+1) 240.1 (100%).

Step 4:1-(4-(5-Methyl-5H-pyrrolo[3,2-d]pyrimidin-4-yloxy)-3-fluorophenyl)-3-(2-phenylacetyl)thiourea(31a)

To a solution of4-(5-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-yloxy)-3-fluorobenzenamine (30)(120.8 mg, 0.5 mmol) and benzyl isothiocyanate (0.1 mL, 0.55 mmol) inTHF (5 mL) was stirred 2 h at room temperature, concentrated underreduced pressure and the residue was subjected to a columnchromatography on silica gel, (eluent EtOAc-hexane 1:1) to afford thetitle compound 31a as a white solid (97.6 mg, 45%). ¹H NMR (400 MHz,DMSO-d₆) δ (ppm): 12.42 (s, 1H), 11.79 (s, 1H), 8.28 (d, J=0.6 Hz, 1H),7.88 (dd, J=2.3 Hz, J=12.1 Hz, 1H), 7.81 (d, J=3.1 Hz, 1H), 7.50 (t,J=8.4 Hz, 1H), 7.44 (dd, J=2.1 Hz, J=8.8 Hz, 1H), 7.33 (m, 4H), 7.28 (m,1H), 6.65 (dd, J=0.6 Hz, J=2.9 Hz, 1H), 4.10 (s, 3H), 3.83 (s, 2H). LRMS(M+1) 436.1 (100%).

Example 291-(4-(5-Ethyl-5H-pyrrolo[3,2-d]pyrimidin-4-yloxy)-3-fluorophenyl)-3-(2-phenylacetyl)thiourea(31b)

Title compound 31b was obtained according to the scheme 5 usingprocedures similar to the ones described for example 28 but using ethyliodide (instead of methyl iodide) in the step 1. Characterization of 31bis provided in table 4.

Example 301-(4-(5-Benzyl-5H-pyrrolo[3,2-d]pyrimidin-4-yloxy)-3-fluorophenyl)-3-(2-phenylacetyl)thiourea(31c)

Title compound 31c was obtained according to the scheme 5 usingprocedures similar to the ones described for the example 28 but usingbenzyl bromide (instead of methyl iodide) in the step 1.Characterization of 31c is provided in table 4.

TABLE 4

31b–c: Examples 29–30 Characterization of 31b–c (examples 29–30) Cpd ExR Name Characterization 31b 29 Et 1-(4-(5-Ethyl-5H- ¹H NMR (400 MHz,DMSO-d₆) pyrrolo[3,2- δ (ppm): 12.4(br, 1H), 11.8(br, d]pyrimidin-4-1H), 8.3(s, 1H), 7.90–7.85(m, yloxy)-3- 2H), 7.54–7.41(m, 2H), 7.40(m,fluorophenyl)-3-(2- 4H), 7.29(m, 1H), 6.63(d, J=3.1phenylacetyl)thiourea Hz, 1H), 4.46(q, J=7.0 Hz, J=14.3 Hz, 2H), 3.83(s,1H), 1.46(t, J=7.0 Hz, 3H). LRMS (M+1) 450.2 (100%). 31c 30 —CH₂Ph1-(4-(5-Benzyl-5H- ¹H NMR (400 MHz, DMSO-d₆) pyrrolo[3,2- δ (ppm):12.34(s, 1H), 11.79(s, d]pyrimidin-4- 1H), 8.3(s, 1H), 8.04(d, J=3.1yloxy)-3- Hz, 1H), 7.8(dd, J=2.3 Hz, J=7.8 fluorophenyl)-3-(2- Hz, 1H),7.4(m, 1H), 7.35–7.76 phenylacetyl)thiourea (m, 11H), 6.7(d, 3.1 Hz,1H), 5.66(s, 2H), 3.82(s, 2H). LRMS (M+1) 512.3 (100%).

Example 311-(4-(7-Methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)-3-fluorophenyl)-3-(2-phenylacetyl)thiourea(36a)

Title compound 36a (scheme 6) was obtained according to the proceduressimilar to the ones described for the example 28 (scheme 5) but using asa starting material 4-chloro-7H-pyrrolo[2,3-d]pyrimidine 32 (instead ofchloride 27). Characterization of 36a is provided in table 5.

Example 321-(4-(7-Ethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)-3-fluorophenyl)-3-(2-phenylacetyl)thiourea(36b)

Title compound 36b was obtained according to the scheme 6 using theprocedures similar to the ones described for the example 31 but usingethyl iodide (instead of methyl iodide) in the step 1. Characterizationof 36b is provided in table 5.

Example 331-(4-(7-Benzyl-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)-3-fluorophenyl)-3-(2-phenylacetyl)thiourea(36c)

Title compound 36c was obtained according to the scheme 6 using theprocedures similar to the ones described for the example 31 but usingbenzyl bromide (instead of methyl iodide) in the step 1.Characterization of 36c is provided in table 5.

TABLE 5

36a–c: Examples 31–33 Characterization of 36a–c (examples 31–33) Cpd ExR Name Characterization 36a 31 Me 1-(4-(7-Methyl-7H- ¹H NMR (400 MHz,DMSO-d₆) δ pyrrolo[2,3-d]pyrimidin-4- (ppm): 12.43(s, 1H), 11.79(s, 1H),yloxy)-3-fluorophenyl)-3- 8.34(s, 1H), 7.87(dd, J=1.8 Hz, (2-phenylacetyl)thiourea J=13.1 Hz, 1H), 7.55(d, J=3.5 Hz, 1H), 7.44(m, 2H),7.33(m, 4H), 7.27(m, 1H), 6.62(d, J=3.5 Hz, 1H), 3.83(m, 5H). LRMS (M+1)436.1 (100%). 36b 32 Et 1-(4-(7-Ethyl-7H- ¹H NMR (400 MHz, DMSO-d₆) δpyrrolo[2,3-d]pyrimidin-4- (ppm): 12.41(br, 1H), 11.78(br,yloxy)-3-fluorophenyl)-3- 1H), 8.32(s, 1H), 7.87(m, 1H), (2-phenylacetyl)thiourea 7.63 (d, J=3.5, Hz, 1H), 7.43 (m, 2H), 7.33(m, 4H),7.27(m, 1H), 6.63(d, J=3.5 Hz, 1H), 4.29(q, J=7.2 Hz, J=14.5 Hz, 2H),3.82(s, 2H), 1.40(t, J=7.2 Hz, 3H). LRMS (M+1) 450.2 (100%). 36c 33—CH₂Ph 1-(4-(7-Benzyl-7H- ¹H NMR (400 MHz, DMSO-d₆) δpyrrolo[2,3-d]pyrimidin-4- (ppm): 12.41(s, 1H), 11.79(s, 1H),yloxy)-3-fluorophenyl)-3- 8.35(s, 1H), 7.87(m, 1H), 7.68(d, (2-phenylacetyl)thiourea J=3.5 Hz, 1H), 7.44(m, 2H), 7.35– 7.23(m, 10H), 6.68(d,3.5 Hz, 1H), 5.48(s, 2H), 3.82(s, 2H). LRMS (M+1) 512.3 (100%).

Example 347-(2-Fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)-N,N-diisobutylthieno[3,2-b]pyridine-2-carboxamide(81) Step 1: Methyl 7-chlorothieno[3,2-b]pyridine-2-carboxylate (37)

To a stirred solution of 2 (7.0 g, 41.3 mmol) in anhydrous THF (100 mL)at −78° C. under a nitrogen atmosphere was added n-BuLi (24.7 mL, 2.5 Min hexanes, 61.8 mmol). After 1 hour, methyl chloroformate (9.6 ml, 124mmol) was added and the reaction mixture was stirred for an extra hourat the same temperature, quenched with excess methanol and allowed towarm to room temperature. The solvent was then evaporated and theresidue was purified by flash chromatography using hexane—AcOEt (70:30)as an eluent. The product from the column was re-crystallized from ethylacetate to afford title compound 37 (4.3 g, 46% yield) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 8.75 (dd, J=0.8 and 4.8 Hz, 1H), 8.26(d, J=0.8 Hz, 1H), 7.74 (dd, J=0.8 and 5.2 Hz, 1H), 3.93 (s, 3H).

Step 2: Methyl7-(2-fluoro-4-nitrophenoxy)thieno[3,2-b]pyridine-2-carboxylate (38)

A mixture of 37 (4.0 g, 17.6 mmol), 2-fluoro-4-nitrophenol (5.5 g, 35.0mmol) and K₂CO₃ (12.1 g, 87.5 mmol) in Ph₂O was heated at 180° C. for 5hours. The mixture was cooled to room temperature, diluted with EtOAcand washed with water. The organic phase was collected, dried overanhydrous sodium sulfate and the solvents were removed under reducedpressure. The residue was purified by flash chromatography usinghexane—AcOEt (70:30) as an eluent. The product from the column wasre-crystallized from a mixture of ethyl acetate-hexanes to afford 38(3.6 g, 59% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ(ppm):8.69 (d, J=5.2 Hz, 1H), 8.47 (dd, J=2.4 and 10.0 Hz, 1H), 8.27 (s, 1H),8.21 (m, 1H), 7.77 (dd, J=8.0 and 9.2 Hz, H), 7.06 (dd, J=0.8 and 5.2Hz, 1H), 3.93 (s, 3H).

Step 3: 7-(2-Fluoro-4-nitrophenoxy)thieno[3,2-b]pyridine-2-carboxylicacid (39)

To a stirred solution of 38 (2.5 g, 7.18 mmol) in THF (50 ml) was addedKOH (14.3 ml, 1.0 N in H₂O, 14.3 mmol). After 4 hours the reactionmixture was concentrated and the resultant residue was dissolved in H₂O(50 ml). The aqueous layer was then washed with ethyl acetate andacidified with 1N HCl (pH=1). The precipitate that formed uponacidification was collected by filtration, washed with water and driedunder high vacuum to afford title compound 39 (2.3 g, 96% yield) as awhite solid. ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 8.6 (d, J=5.2 Hz, 1H),8.47 (dd, J=2.8 and 10.4 Hz, 1H), 8.20 (m, 1H), 8.17 (s, 1), 7.76 (dd,J=8.0 and 8.8 Hz, 1H), 7.04 (d, J=5.2 Hz, 1H).

Step 4: 7-(2-Fluoro-4-nitrophenoxy)thieno[3,2-b]pyridine-2-carbonylchloride (40)

To a solution of 39 (2.0 g, 5.98 mmol) in anhydrous CH₂Cl₂ (30 ml) underan atmosphere of nitrogen, was added oxalyl chloride (2.6 ml, 29.8mmol). After stirring for 2 hours the solvent was evaporated, anhydroustoluene (10 mL) was added and the resultant mixture was evaporated(procedure of addition of toluene followed by evaporation was performedtwice) to afford title compound 40 (2.2 g, 94% yield) as a white solid.The product was used without further purification and characterizationand was assumed to be the mono-HCl salt.

Step 5:7-(2-Fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)-N,N-diisobutylthieno[3,2-b]pyridine-2-carboxamide(81)

To a solution of 40 (150 mg, 0.385 mmol) and TEA (107 μl, 0.771 mmol) inanhydrous CH₂Cl₂ under an atmosphere of nitrogen was addeddiisobutylamine (67 μL, 0.385 mmol). After stirring for 1 hour, methanol(2 mL) was added followed by iron powder (150 mg) and HCl (conc., 0.4mL). The reaction mixture was stirred for additional 2 hours and thenpartitioned between ethyl acetate (20 mL) and a mixture of H₂O (20 mL)and NH₄OH (2 mL). Organic phase was collected, washed with brine, driedover anhydrous MgSO₄, filtered and evaporated. The residue was treatedwith 2-phenylacetyl isothiocyanate (102 mg, 0.58 mmol) in THF (2 mL),the resultant mixture was allowed to stand for 2 hours at ambienttemperature, quenched with methanol (5.0 mL), loaded onto 5 ml of silicagel and purified by flash chromatography using hexane—AcOEt (70:30) asan eluent, to afford title compound 81 (41 mg, 18%) as a white solid. ¹HNMR (400 MHz, CD₃OD) δ (ppm): 8.54 (d, J=5.6 Hz, 1H), 8.08 (dd, J=2.0and 12.0 Hz, 1H), 7.69 (s, 1H), 7.38-7.49 (m, 2H), 7.28-7.35 (m, 5H),6.77 (dd, J=1.2 and 5.6 Hz, 1H), 3.77 (s, 2H), 3.46 (bs, 4H), 2.18 (bs,1H), 2.02 (bs, 1H), 1.02 (bs, 6H), 0.87 (bs, 6H). LRMS (M+1):592.7(calcd), 593.3 (found).

TABLE 6 Characterization of compounds 8m-y (examples 35-47)

8m-y: Examples 35-47 Cpd Ex R Name Characterization 8m 35

7-[2-Fluoro-4-(3- phenylacetyl- thioureido)-phenoxy]-thieno[3,2-b]pyridine-2- carboxylic acid furan-2- ylmethyl-methyl-amide¹H NMR(400 MHz, DMSO-d₆) δ(ppm): 12.49(s, 1H), 11.82(s, 8.59(d, J=5.6Hz, 1H), 7.92-8.05(m, 2H), 7.67(bs, 1H), 7.54(m, 2H), 7.25-7.37 (m, 5H),6.75(d, J=0.8, 5.2 Hz, 1H), 6.46(s, 2H), 4.74(bs, 2H), 3.83(s, 2H),3.27(bs, 1.5H), 2.99(bs, 1.5H). LRMS(M + 1):574.6(cald), 575.2(found).8n 36

7-[2-Fluoro-4-(3- phenylacetyl- thioureido)-phenoxy]-thieno[3,2-b]pyridine-2- carboxylic acid(2- diisopropylamino-ethyl)-amide, formate salt 12.45(s, 1H), 11.78(s, 1H), 8.92(t, J=5.6 Hz,1H), 8.53(d, J=5.6 Hz, 1H), 8.16(s, 1H), 8.12(s, 1H), 7.99(m, 1H), 7.50(m, 2H), 7.21-7.30(m, 5H), 6.69(d, J=5.2 Hz, 1H), 3.79(s, 2H), 3.22(m,2H), 2.97(m, 2H), 2.55(t, J7.6Hz, 2H), 0.964(d, J=6.4 Hz, 12H).LRMS(M + 1) .607.8(calcd.), 608.3(found). 8o 37

1-{3-Fluoro-4-[2- (pyrrolidine-1- carbonyl)-thieno[3,2-b]pyridin-7-yloxy]- phenyl}-3-phenylacetyl- thiourea ¹H NMR(400 MHz,DMSO-d₆) δ(ppm): 12.48(s, 1H), 11.82(s, 1H), 8.58(d, J=5.3 Hz, 1H),8.03(m, 2H), 8.00(s, 1H), 7.53 (m, 2H), 7.33(m, 4H), 7.28(m, 1H),6.73(d, J=5.3 Hz, 1H), 3.86(t, J=6.4 Hz, 2H), 3.83(s, 2H), 3.53(t,J=6.84 Hz, 2H), 1.95-1.86(m, 4H). LRMS(M + 1) .534.6(calcd.),535.2(found). 8p 38

(R)-N-(3-Fluoro-4-(2- (3-hydroxypyrrolidine- 1-carbonyl)thieno[3,2-b]pyridin-7- yloxy)phenylcarbamothioyl)- 2-phenylacetamide ¹H NMR(400MHz, DMSO-d₆) δ(ppm): 12.48(s, 1H), 11.81(s, 1H), 8.59(d, J=5.6 Hz, 1H),8.04(m, 2H), 7.54(m, 2H), 7.22-7.34(m, 5H), 6.74(d, J=5.2 Hz, 1H),5.07(bs, 1H), 4.36(bd, J=19.6 Hz, 1H), 3.99 (m, 1H), 3.82(s, 2H),3.38-3.68 (m, 3H), 1.80-2.06(m, 2H). MS(m/z): 551.1 (M + H)(found). 8q39

(S)-N-(3-Fluoro-4-(2- (3-hydroxypyrrolidine- 1-carbonyl)thieno[3,2-b]pyridin-7-yloxy) phenylcarbamothioyl)- 2-phenylacetamide ¹HNMR(DMSO-d₆) δ(ppm): 12.51(s, 1H), 11.84(s, 1H), 8.62(d. 1H, J=5.3 Hz),8.08- 8.01(m, 2H), 7.56-7.52(m, 2H), 7.36-7.31(m, 4H), 7.28-7.24(m, 1H),6.77(d, 1H, J=5.7 Hz), 4.38-4.32(m, 1H), 4.00-3.92(m, 1H), 3.81(s, 2H),3.67-3.55(m, 4H), 2.06-1.83(m, 2H). MS (m/z): 551.1(M + H)(found). 8r 40

(S)-1-(7-(2-Fluoro-4-(3- (2- phenylacetyl)thioureido)phenoxy)thieno[3,2- b]pyridine-2- carbonyl)pyrrolidine-2- carboxamideLRMS(M + 1) 577.6(calcd.), 578.3(found). 8s 41

7-[2-Fluoro-4-(3- phenylacetyl- thioureido)-phenoxy]-thieno[3,2-b]pyridine-2- carboxylic acid(2- cyano-ethyl)-cyclopropyl-amide LRMS(M + 1): 573.7(caled.), 574.2(found). 8t 42

7-[2-Fluoro-4-(3- phenylacetyl- thioureido)-phenoxy]-thieno[3,2-b]pyridine-2- carboxylic acid(2- dimethylamino-ethyl)-amide,formate salt LRMS(M + 1): 551.7(cald), 552.2(found) 8u 43

7-[2-Fluoro-4-(3- phenylacetyl- thioureido)-phenoxy]-thieno[3,2-b]pyridine-2- carboxylic acid bis-(2- methoxy-ethyl)-amideLRMS(M + 1): 596.7(cald), 597.3(found). 8v 44

7-[2-Fluoro-4-(3- phenylacetyl- thioureido)-phenoxy]-thieno[3,2-b]pyridine-2- carboxylic acid benzylamide LRMS(M + 1):570.7(caled), 571.3(found). 8w 45

7-[2-Fluoro-4-(3- phenylacetyl- thioureido)-phenoxy]- thieno[3,2-b]pyridine-2- carboxylic acid(2- cyano-ethyl)-phenyl- amideLRMS(M + 1): 609.7(caled.), 610.2 found. 8x 46

(R)-N-(1-amino-4- methyl-1-oxopentan-2- yl)-7-(2-fluoro-4-(3-(2-phenylacetyl)thioureido) phenoxy)thieno[3,2- b]pyridine-2- carboxamideLRMS(M + 1): 593.6(caled), 594.2(found). 8y 47

7-[2-Fluoro-4-(3- phenylacetyl- thioureido)-phenoxy]-thieno[3,2-b]pyridine-2- carboxylic acid(2,5- dimethyl-2H-pyrazol-3-yl)-amide LRMS(M + 1): 574.6(caled), 575.2(found)

Example 48N-(4-(2-Bromothieno[3,2-b]pyridin-7-yloxy)-3-fluorophenylcarbamothioyl)-2-phenylacetamide(44) Step 1. 2-Bromo-7-chlorothieno[3,2-b]pyridine (41)

To a stirred solution of the chloride 2 (10.12 g, 5.59 mmol) in dry THF(200 ml) at −78° C. was added n-BuLi (24 ml, 76.7 mmol, 2.5 M solutionin hexanes) and the resultant suspension was stirred for 15 minutes.Bromine (18.9 g, 120 mmol) was added slowly and the reaction mixture wasstirred for additional 30 min, quenched with water and diluted withEtOAc. The organic phase was collected, dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure. Purificationby column chromatography (9:1 EtOAc/hexane) afforded title compound 41(10.5 g, 71% yield) as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ (ppm):8.62 (d, J=5.09 Hz, 1H), 7.92 (s, 1H), 7.59 (d, J=5.09 Hz, 1H).

Step 2. 2-Bromo-7-(2-fluoro-4-nitrophenoxy)thieno[3,2-b]pyridine (42)

A mixture of the bromide 41 (5.1 g, 20.5 mmol), potassium carbonate(5.65 g, 4 mmol) and 2-fluoro-4-nitrophenol (4.82 g, 30.7 mmol) washeated at 190° C. in diphenyl ether (25 ml) for 3 hrs. After cooling toroom temperature it was diluted with DCM and filtered. The filtrate wasconcentrated under reduced pressure and the residue was purified bycolumn chromatography (eluent EtOAc:hexane, 3:1) to afford titlecompound 42 as a yellow solid (5.4 g, 71% yield). ¹H NMR (400 MHz,DMSO-d₆) δ (ppm): 8.55 (d, J=5.28 Hz, 1H), 8.46 (dd, J=2.5 and 10.4 Hz,1H), 8.19 (d, J=8.8 Hz, 1H), 7.87 (s, 1H), 7.72 (t, J=8.4 Hz), 6.99 (d,J=5.47 Hz, 1H).

Steps 3-4.1-(4-(2-Bromothieno[3,2-b]pyridin-7-yloxy)-3-fluorophenyl)-3-(2-phenylacetyl)thiourea(44)

To a solution of the nitro compound 42 (100 mg, 0.27 mmol) in THF (2 ml)and water (0.5 ml) was added SnCl₂×2H₂O (76.99 mg, 1.5 eq, 0.41 mmol)and the reaction mixture was refluxed for 3 hrs, cooled to roomtemperature, diluted with EtOAc and washed with conc. ammonium hydroxidesolution. EtOAc-extract was collected and the aqueous fractions werecombined and washed with DCM. DCM extract was combined with theAcOEt-extract, the mixture was dried over sodium sulfate, filtered andevaporated to form the amine 43 (92 mg, 100%), which was used withoutany further purification.

To a solution of the amine 43 (92 mg, 0.27 mmol) in THF (10 ml) wasadded benzyl isothiocyanate (72 mg, 1.5 eq, 0.407 mmol). The reactionmixture was stirred for 1 hr at room temperature, concentrated underreduced pressure and the residue was purified by column chromatography(7:3 hexane:EtOAc to 1:1 MeOH:EtOAc) to afford the title compound 44 asa white solid (28 mg, 20% yield). ¹H NMR (400 MHz, DMSO-d₆) δ (ppm):12.48 (s, 1H), 11.81 (s, 1H), 8.55-8.52 (m, 1H), 8.01 (d, J=11.9 Hz,1H), 7.85 (s, 1H), 7.55-7.49 (m, 2H), 7.45-7.19 (m, 5H), 6.73 (d, J=5.7Hz, 1H), 3.82 (s, 2H). MS (m/z): 518.2/520.2 (M+H).

Example 49N-(3-Fluoro-4-(2-(6-methoxypyridin-3-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(47a) Step 1.7-(2-Fluoro-4-nitrophenoxy)-2-(6-methoxypyridin-3-yl)thieno[3,2-b]pyridine(45)

A mixture of the nitro compound 42 (500 mg, 1.36 mmol),6-methoxypyridin-3-ylboronic acid (312 mg, 2.04 mmol) and CsF (620 mg,4.08 mmol) were suspended in DME (12 ml) and NaHCO₃ (342 mg, 4.08 mmol),dissolved in the minimum amount of water, was added. The mixture wasde-aerated by bubbling N₂ through the solution for 10 min, heated at 80°C. for 3 hrs and concentrated to dryness. The formed residue wasdissolved in DCM and washed with water. The DCM was collected, driedover sodium sulfate, filtered and the DCM was removed by evaporation.The resultant solid was triturated with Et₂O to afford the titlecompound 45 (176 mg, 32% yield), which was used without furtherpurification. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 8.71 (m, 1H), 8.56 (m1H), 8.46 (m, 1H), 8.22 (m, 2H), 8.01 (s, 1H), 7.72 (t, J=8.6 Hz, 1H),6.99 (d, J=5.47 Hz, 1H), 6.90 (m, 1H), 3.97 (s, 3H).

Step 2.N-(3-Fluoro-4-(2-(6-methoxypyridin-3-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(47a)

To a solution of 45 (176 mg, 0. 44 mmol) in MeOH (10 ml) and THF (10 ml)at 0° C. was added NiCl₂×6H₂O (210 mg, 0.89 mmol) and NaBH₄ (65 mg, 1.76mmol). The reaction mixture was stirred for 1 hr, concentrated todryness and the resultant solid was dissolved in 1 M HCl. The acidicsolution was then made basic with aqueous ammonium hydroxide andextracted with EtOAc. The organic phase was collected, dried overanhydrous sodium sulfate and filtered. The filtrate was evaporated underreduced pressure and the residue was triturated with Et₂O to afford theamine 46 as a white solid which was used immediately in the next step.

To a suspension of the amine 46 (162 mg, 0.44 mmol) in THF (7 ml) wasadded 2-phenylacetyl isothiocyanate (117 mg, 0.66 mmol). The reactionmixture was stirred for 1 hr, concentrated under reduced pressure andthe residue was purified by column chromatography (eluent EtOAc-MeOH,95:5); a solid was obtained which was triturated with Et₂O to affordtitle compound 47a (80 mg, 33% yield). ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 12.50 (s, 1H), 11.85 (s, 1H), 8.70 (s, 1H), 8.68 (d, J=6.07 Hz,1H), 8.28 (m, 1H), 8.10 (s, 2H), 7.59 (s, 2H), 7.34-7.27 (m, 5H), 7.01(d, J=8.61 Hz, 1H), 6.93 (d, J=5.7 Hz, 1H), 3.93 (s, 3H), 3.83 (s, 2H).

Examples 50-54

Examples 50-54 (compounds 47b-f) were prepared similarly to the compound47a (example 49) according to the scheme 9.

TABLE 7 Characterization of compounds 47b-f(examples 50-54)

47b-f: Examples 50-54 Cpd Ex R Name Characterization 47b 50

N-(3-Fluoro-4-(2- (6-fluoropyridin-3- yl)thieno[3,2- b]pyridin-7-yloxy)phenylcarbamo- thioyl)-2- phenylacetamide ¹H NMR(400 MHz, DMSO-d₆)δ ppm): 12.46(s, 1H), 11.82(s, 1H), 8.79(m, 1H), 8.55(d, J=5.48 Hz, 1H),8.50(m, 1H), 8.19(s, 1H), 8.02(d, J=13 Hz, 1H), 7.53(m, 1H),7.37-7.26(m,6H), 6.68(m, 1H), 6.68(m, 1H), 3.82(s, 2H). 47c 51

N-(3-Fluoro-4-(2- (pyrimidin-5- yl)thieno[3,2- b]pyridin-7-yloxy)phenylcarbamo- thioyl)-2- phenylacetamide dihydo chloride. ¹HNMR(400 MHz, DMSO-d₆) δ ppm): 12.48(s, 1H), 11.83(s, 1H), 9.2(bs, 3H)8.63(m, 1H), 8.34(s, 1H), 8.03(d, J=11 Hz, 1H), 7.55 (m, 2H), 7.30(m,6H), 6.68(m, 1H), 3.82(s, 2H). 47d 52

N-(3-Fluoro-4-(2- (1-methyl-1H- pyrrole-2- yl)thieno[3,2- b]pyridin-7-yloxy)phenylcarbamo- thioyl)-2- phenylacetamide ¹H NMR(400 MHz, DMSO-d₆)δ (ppm): 8.46(d, J=5.9 Hz, 1H), 8.04 (m, 1H), 7.59(s, 1H), 7.51(m, 2H),7.3-7.2(m, 6H), 7.01(s, 1H) 6.58 (d, J=5.9 Hz, 1H), 6.53(m, 1H), 6.10(m,1H), 3.87(s, 3H), 3.81(s, 2H). 47e 53

N-(3-Fluoro-4-(2- (furan-3- yl)thieno[3,2- b]pyridin-7-yloxy)phenylcarbamo- thioyl)-2- phenylacetamide ¹H NMR(DMSO) δ(ppm):12.49(s, 1H), 11.84(s, 1H), 8.49(d, J=5.5 Hz, 1H), 8.36(s, 1H), 8.00(d,J= 11.3 Hz, 1H), 7.85-7.83(m, 1H), 7.82(s, 1H), 7.52-7.5 1(m, 2H), 7.34-7.33(m, 4H), 7.28-7.26(m, 1H), 7.09 (brs, 1H), 6.62(d, J=5.3 Hz, 1H),3.82(s, 2H), MS(m/z) 504.0(M + H) 47f 54

1-(3-Fluoro-4-(2- (4-methyithiophen- 3-yl)thieno[3,2- b]pyridin-7-yloxy)phenyl)-3- (2- phenylacetyl)thiourea ¹H NMR(DMSO) δ(ppm): 12.49(s,1H), 11.84(s, 1H), 8.52(d, J=5.5 Hz, 1H), 8.01(d, J=5.6 Hz, 1H), 7.94(d,J=2.7 Hz, 1H), 7.70(s, 1H), 7.54-7.52(m, 2H), 7.41-7.40(m, 1H),7.35-7.34(m, 3H), 7.33(s, 1H), 7.27(m, 1H), 6.64(dd, J=4.7 Hz, 1H),3.82(s, 2H), 2.43(s, 3H), MS (m/z) 534.0(M + H).

Example 55N-(3-Fluoro-4-(2-(4-(methylsulfonyl)phenyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(50) Step 1.7-(2-Fluoro-4-nitrophenoxy)-2-(4-(methylsulfonyl)phenyl)thieno[3,2-b]pyridine(48)

To a solution of 42 (461 mg, 1.3 mmol, scheme 8) in DME (4 mL) was added4,4,5,5-tetramethyl-2-(4-(methylsulfonyl)phenyl)-1,3,2-dioxaborolane(500 mg, 2.5 mmol), CsF (391 mg, 3.8 mmol), Pd(PPh₃)₄ (72 mg, 63 μmol)and NaHCO₃ (315 mg, 3.8 mmol) pre-dissolved in H₂O (1 ml). The reactionmixture was purged with nitrogen and refluxed for 2 hours. The DME wasremoved under reduced pressure and the aqueous layer was extracted withEtOAc. The extract was dried over sodium sulphate, filtered andevaporated to form a residue which was purified by column chromatography(eluent EtOAc/hexane, 1:1) to afford the title compound 48 (97 mg, 18%yield) as a white solid. ¹HNMR (DMSO) δ (ppm): 8.63 (d, J=1.2 Hz, 1H),8.49 (d-d, J=2.7 Hz, 1H), 8.33 (s, 1H), 8.22-8.19 (m, 2H), 8.16 (s, 2H),8.02 (d, J=8.6 Hz, 2H), 7.75 (t, J=8.0 Hz, 1H), 7.77-7.58 (m, 2H),7.58-7.50 (m, 2H), 6.97 (d, J=5.5 Hz, 1H), 3.33 (s, 3H), MS (m/z): 444.8(M+H).

Step 2.3-Fluoro-4-(2-(4-(methylsulfonyl)phenyl)thieno[3,2-b]pyridin-7-yloxy)benzenamine(49)

Nitro compound 48 (97 mg, 2 mmol) was dissolved in a mixture of THF (7mL) and MeOH (15 mL); NiCl₂×6H₂O (130 mg, 0.5 mmol) was added and thesolution was cooled to 0° C. To the cooled mixture NaBH₄ (42 mg, 1.1mmol) was added portion wise. The reaction was stirred for 20 min andquenched with 2 M HCl. The solvents were removed under reduced pressureand the residue was treated with concentrated ammonium hydroxidesolution (pH 10) and extracted with EtOAc. The organic extract was driedover anhydrous sodium sulfate, filtered and evaporated. The residue waspurified by column chromatography (eluent EtOAc) to afford the titlecompound 49 (46.7 mg, 51% yield) as a white solid. ¹H NMR (DMSO) δ(ppm): 8.52 (d, J=5.5 Hz, 1H), 8.25 (s, 1H), 8.15 (d, J=8.4 Hz, 2H),8.03 (d, J=8.4 Hz, 2H), 7.63-7.58 (m, 2H), 7.56-7.52 (m, 2H), 7.13 (t,J=8.6 Hz, 1H), 6.61 (d, J=2.2 Hz, 1H), 6.56 (dd, J=10 Hz, 1H), 6.46 (dd,J=5.7 Hz, 1H), 5.57 (s, 2H), 3.29 (s, 3H), MS (m/z): 414.8 (M+H).

Step 3.N-(3-Fluoro-4-(2-(4-(methylsulfonyl)phenyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(50)

To a solution of 49 (46.7 mg, 0.1 mmol) in dry THF (5 mL),2-phenylacetyl isothiocyanate (40 mg, 0.2 mmol) was added and thereaction was allowed to stir for 30 minutes. The THF was removed underreduced pressure and the resultant product was purified by columnchromatography on silica gel, eluent hexane/EtOAc (1:1), to afford thetitle compound 50 (35.4 mg, 53% yield). ¹HNMR (DMSO) δ (ppm): 12.49 (s,1H), 11.85 (s, 1H), 8.57 (d, J=5.5 Hz, 1H), 8.30 (s, 1H), 8.17 (d, J=8.4Hz, 2H), 8.02 (d, J=8.4 Hz, 2H), 7.63-7.52 (m, 5H), 7.34 (d, J=4.1 Hz,2H), 6.71 (d, J=5.3 Hz, 1H), 3.82 (brs, 2H), 3.27 (s, 3H) MS (m/z) 592.0(M⁺).

Example 561-(3-Fluoro-4-(2-(4-(morpholinomethyl)phenyl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-3-(2-phenylacetyl)thiourea(55) Step 1.(4-(7-(2-Fluoro-4-nitrophenoxy)thieno[3,2-b]pyridin-2-yl)phenyl)methanol(51)

To a solution of 42 (1.0 g, 2.71 mmol) in dry DME (20 ml) was added4-(hydroxymethyl)phenylboronic acid (823 mg, 5.4 mmol), NaHCO₃ (682 mg,8.13 mmol), CsF (820 mg, 5.4 mmol) and water (10 mL) and the reactionmixture was refluxed under nitrogen for 2 hrs. After cooling to roomtemperature the DME was removed under reduced pressure, the residue wasdissolved in EtOAc and the organic solution was washed with water, driedover anhydrous sodium sulfate, filtered and evaporated. The resultantsolid residue was triturated with Et₂O to afford the title compound 51as a white solid (880 mg, 82% yield). MS (m/z): 397.1 (M+H).

Step 2.2-(4-(Chloromethyl)phenyl)-7-(2-fluoro-4-nitrophenoxy)thieno[3,2-b]pyridine(52)

The alcohol 51 (880 mg, 2.22 mmol) was suspended in SOCl₂ (10 ml) andthe reaction mixture was refluxed for 1 hour, cooled and carefullypoured onto ice/water. A precipitate was formed which was collected byfiltration, washed with additional cold water and dried under vacuum toafford the title compound 52 (919 mg, 100% yield), which was usedwithout additional purification. MS (m/z): 415.1(100%) (M+H), 417.1(36%) (M+H).

Step 3.7-(2-Fluoro-4-nitrophenoxy)-2-(4-(morpholinomethyl)phenyl)thieno[3,2-b]pyridine(53)

To a suspension of 52 (823 mg, 1.82 mmol) in DMF (10 ml) was addedmorpholine (317 mg, 3.65 mmol) and the reaction mixture was heated for 4hours at 60° C., the solvent was removed under reduced pressure and theresidual solid was triturated with EtOAc and collected by filtration. Itwas further washed with EtOAc until no color was observed in thefiltrate, to form the title compound 53 (800 mg, 94% yield), which wasused without additional purification. ¹HNMR (DMSO) δ (ppm): 8.57 (d,J=4.7 Hz, 1H), 8.46 (dd, J=2.7 and 10.4 Hz, 1H), 8.18 (m, 1H), 8.07 (s,1H), 7.83 (d, J=12.2 Hz, 1H), 7.71 (t, J=8.02 Hz, 1H), 7.42 (d, J=8.2Hz, 1H), 6.91 (d, J=5.3 Hz, 1H), 3.56 (m, 4H), 3.51 (m, 2H), 3.33 (m,3.33 (m, 2H), 2.50 (m, 2H).

Step 4.1-(3-Fluoro-4-(2-(4-(morpholinomethyl)phenyl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-3-(2-phenylacetyl)thiourea(55)

To a solution of 53 (1.1 g, 2.37 mmol) in MeOH (20 mL) and THF (20 mL)at 0° C. was added NiCl₂×6H₂O (1.12 g, 4.73 mmol) and NaBH₄ (350 mg,9.48 mmol). The reaction mixture was allowed to stir for 1 hr, solventswere removed under reduced pressure and the resultant solid residue wasdissolved in 1 M HCl. This solution was made basic with concentratedaqueous ammonium hydroxide and extracted with EtOAc. The organic phasewas collected, dried over anhydrous sodium sulfate and filtered. Thefiltrate was evaporated under reduced pressure and the resultant solidwas triturated with Et₂O to afford the amine 54 as a white solid (1.02g, 100% yield), which was used in the next step without furtherpurification.

To a suspension of the amine 54 (1.02 g, 2.34 mmol) in THF (10 mL) wasadded 2-phenylacetyl isothiocyanate (622 mg, 3.52 mmol) and the reactionmixture was stirred for 1 hr at room temperature, concentrated underreduced pressure and purified by column chromatography (eluentEtOAc:MeOH, 95:5) to afford title compound 55 as a yellow powder (288mg, 12% yield). ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.48 (s, 1H), 11.84(s, 1H), 8.63 (m, 1H), 8.18 (s, 1H), 8.01 (d, J=7.8 Hz, 2H), 7.75 (m,2H), 7.57 (s, 2H), 7.33 (m, 4H), 6.80 (d, J=11.7 Hz, 2H), 3.83 (s, 5H),3.37 (d, J=11.7 Hz, 2H), 3.12 (m, 2H). MS (m/z) 613.3 (M+H).

Example 571-(3-Fluoro-4-(2-(3-morpholinoprop-1-ynyl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-3-(2-phenylacetyl)thiourea(58) Step 1.7-(2-Fluoro-4-nitrophenoxy)-2-(3-morpholinoprop-1-ynyl)thieno[3,2-b]pyridine(56)

To a solution of bromide 42 (100 mg, 0.27 mmol) in THF (5 ml) was added4-(prop-2-ynyl)morpholine (68 mg, 0.54 mmol) [H-W. Tsou, et. al. J. Med.Chem., 2001, 44, 2719-2734], triethylamine (68 mg, 0.67 mmol), CuI (5mg, 0.03 mmol) and Pd(PPh₃)₂Cl₂ (5.3 mg, 7.56 μmol). The reactionmixture was degassed with nitrogen and refluxed for 2 hrs, cooled toroom temperature and adsorbed onto silica. Purification by columnchromatography (eluent EtOAc) afforded the title compound 56 as a beigesolid (88 mg, 79%). MS (m/z): 397.1 (M+H).

Steps 2-3.1-(3-Fluoro-4-(2-(3-morpholinoprop-1-ynyl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-3-(2-phenylacetyl)thiourea(58)

To a solution of the nitro compound 56 (300 mg, 0.724 mmol) in THF (10mL) and NH₄Cl (6 mL) was added SnCl₂×2H₂O (489 mg, 2.17 mmol) and thereaction mixture was refluxed for 3 hrs. After cooling the mixture wasdiluted with EtOAc and washed with concentrated aqueous ammoniumhydroxide. EtOAc phase was separated and the aqueous phase was extractedwith DCM. Both EtOAc phase and DCM extract were combined, dried overanhydrous sodium sulfate and filtered. The filtrate was evaporated todryness to afford the amine 57 (277 mg, 100% yield), which was usedwithout further purification.

To a solution of the amine 57 (270 mg, 0.74 mmol) in THF (10 mL) wasadded 2-phenylacetyl isothiocyanate (188 mg, 1.06 mmol) and the reactionmixture was stirred for 1 hr, concentrated under reduced pressure andpurified by column chromatography (eluent EtOAc) to afford titlecompound 58 (37 mg, 10% yield) as a white solid. ¹H NMR (400 MHz,DMSO-d₆) δ (ppm): 12.47 (s, 1H), 11.82 (s, 1H), 8.55 (d, J=5.3 Hz, 1H),8.01 (d, J=13.2 Hz, 1H), 7.79 (s, 1H), 7.52 (s, 1H), 7.33 (m, 4H), 7.28(m, 1H), 6.72 (d, J=5.3 Hz, 1H), 3.82 (s, 2H), 3.64 (s, 2H), 3.61 (m,5H), 2.51 (m, 4H). MS (m/z): 561.3 (M+H).

Example 582-((4-(7-(2-Fluoro-4-nitrophenoxy)thieno[3,2-b]pyridin-2-yl)phenyl)methylamino)ethanol(63) Step 1.2-{4-[7-(2-Fluoro-4-nitro-phenoxy)-thieno[3,2-b]pyridin-2-yl]-benzylamino}-ethanol(59)

To a suspension of the chloride 52 (500 mg, 1.1 mmol) in DME (10 mL) wasadded ethanolamine (336 mg, 5.5 mmol). The reaction mixture refluxed for2 hrs, the solvent was removed under reduced pressure; the residue wasdissolved in EtOAc and washed with water. The organic phase wascollected, dried over sodium sulfate, filtered and evaporated. Theremaining solid was triturated with Et₂O to afford the title compound 59as a yellow solid (200 mg, 41% yield). ¹H NMR (DMSO) δ (ppm): 8.57 (d,J=5.5 Hz, 1H), 8.47 (dd, J=2.7 and 10.4 Hz, 1H), 8.21 (m, 1H), 8.17 (s,1H), 7.83 (d, J=8.0 Hz, 1H), 7.71 (t, J=8.6 Hz, 1H), 7.44 (d, J=8.0 Hz,1H), 6.91 (d, J=5.5 Hz, 1H), 4.48 (t, J=5.5 Hz, 1H), 3.75 (s, 2H), 3.45(q, J=5.6 Hz, 2H), 3.33 (m, 1H), 3.15 (d, J=5.1 Hz, 2H), 2.56 (t, J=5.7Hz, 2H).

Step 2. Carbonic acid2-(tert-butoxycarbonyl-{4-[7-(2-fluoro-4-nitro-phenoxy)-thieno[3,2-b]pyridin-2-yl]-benzyl}-amino)-ethylester tert-butyl ester (60)

To a solution of 59 (200 mg, 0.45 mmol) in DCM (7 mL) at roomtemperature was added triethylamine (188 mg, 1.82 mmol), DMAP (cat) andBoc₂O (355 mg, 1.82 mmol). The reaction mixture was stirred at roomtemperature overnight, the DCM was removed under reduced pressure andthe residue was dissolved in EtOAc, washed sequentially with dilute HClsolution, saturated NaHCO₃ and brine, dried over anhydrous sodiumsulfate and filtered. The filtrate was evaporated and the residue waspurified by column chromatography (eluent EtOAc:hexane, 3:7) to affordtitle compound 60 (200 mg, 69% yield) as a yellow oil. ¹H NMR (DMSO) δ(ppm): 8.58 (d, J=5.3 Hz, 1H), 8.47 (dd, J=2.7 and 10.3 Hz, 1H), 8.21(m, 1H), 8.09 (s, 1H), 7.87 (m, 2H), 7.72 (t, J=8.4 Hz, 1H), 7.33 (d,J=8.2 Hz, 2H), 6.91 (d, J=5.3 Hz, 1H), 4.44 (s, 2H), 4.07 (t, J=5.5 Hz,2H), 3.40 (m, 2H), 1.36 (m, 18H).

Steps 3-4. Carbonic acid2-[tert-butoxycarbonyl-(4-{7-[2-fluoro-4-(3-phenylacetyl-thioureido)-phenoxy]-thieno[3,2-b]pyridin-2-yl}-benzyl)-amino]-ethylester tert-butyl ester (62)

To a solution of 60 (500 mg, 1.1 mmol) in MeOH (10 mL) at 0° C. wasadded NiCl₂×6H₂O (148 mg, 0.63 mmol) and NaBH₄ (46 mg, 1.24 mmol). Thereaction mixture was allowed to stir for 1 hr, concentrated to drynessand the resultant solid was dissolved in 1 M HCl. The acidic solutionwas then made basic with concentrated ammonium hydroxide solution andextracted with EtOAc. The organic phase was collected, dried overanhydrous sodium sulfate and filtered. The filtrate was evaporated underreduced pressure and the resultant solid was triturated with Et₂O toafford the crude amine 61 as a white solid (190 mg, 100% yield), whichwas used for the next step without characterization and additionalpurification.

To a suspension of the amine 61 (190 g, 0.31 mmol) in THF (7 mL) wasadded 2-phenylacetyl isothiocyanate (118 mg, 0.62 mmol) and the reactionmixture was stirred for 1 hr at room temperature, concentrated underreduced pressure and purified by column chromatography (eluentEtOAc-MeOH, 6:4) to afford title compound 62 as a yellow powder (190 mg,77% yield). ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.48 (s, 1H), 11.83 (s,1H), 8.51 (s, 1H), 8.04 (s, 1H), 8.01 (d, J=11.7 Hz, 1H), 7.86 (d, J=7.7Hz, 2H), 7.52 (m, 2H), 7.34 (m, 6H), 7.32 (m, 1H), 6.64 (d, J=5.5 Hz,1H), 4.43 (s, 2H), 4.07 (t, J=5.3 Hz, 2H), 3.81 (s, 2H), 3.44 (m, 2H),1.37 (m, 18H).

Step 5.1-(3-Fluoro-4-(2-(4-((2-hydroxyethylamino)methyl)phenyl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-3-(2-phenylacetyl)thiourea(63)

To a solution of 62 in DCM (190 mg, 0.24 mmol) was added TFA (excess) atroom temperature and the reaction mixture was stirred for 3 hrs,evaporated under reduced pressure and the residual solid was trituratedwith Et₂O to afford the title compound 63 as the di-TFA salt (100 mg,51% yield). ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.49 (s, 1H), 11.84 (s,1H), 8.89 (s, 1H), 8.53 (d, J=5.1 Hz, 1H), 8.14 (s, 1H), 8.01 (m, 1H),7.62 (dd, J=2.5 and 7.7 Hz, 2H), 7.54 (d, J=2.7 Hz, 2H), 7.33 (m, 4H),7.28 (m, 1H), 6.67 (d, J=5.5 Hz, 1H), 4.64 (m, 1H), 4.30 (m, 1H), 4.22(t, J=5.3 Hz, 2H), 3.82 (s, 2H), 3.63 (t, J=5.3 Hz, 2H), 2.98 (m, 1H).MS (m/z) 587.0 (M+H).

N-(3-Bromobenzyl)-2-methoxyethanamine (64)

To a solution of 2-methoxyethanamine (900 mg, 12 mmol) in DME (15 mL)was added 3-bromobenzylbromide (2.5 g, 10 mmol) and the reaction mixturewas stirred at 40° C. (scheme 14). After 30 minutes, Et₃N (1.01 g, 10mmol) was added and the reaction was allowed to stir for another 10minutes, filtered and the filtrate was concentrated to afford bromide 64as a colorless oil (2.0 g, 80% yield). MS (m/z): 244.1/246.1 (M+H).

tert-Butyl 3-bromobenzyl(2-methoxyethyl)carbamate (65)

To a solution of compound 64 (997 mg, 4 mmol) in CH₂Cl₂ (12 mL),di-tert-butylcarbonate (1.8 g, 8 mmol) was added and the reactionmixture was stirred for 3 hrs (scheme 14). DMAP (cat.) was added to thesolution and the reaction mixture was allowed to stir for additional 76hours. Solvent was removed under reduced pressure and the crude productwas purified by column chromatography, eluent EtOAc/hexane (1:10) toafford the title compound 65 (778 mg, 56% yield) as a colorless oil. MS(m/z): 368.1/370.1 (M+Na).

TABLE 8 Aryl bromides 66-70 prepared according to the scheme 14 Aminereagent used to obtain the Characterization aryl Cpd Aryl bromideChemical name MS(m/z) bromides 66

tert-Butyl 3- bromobenzyl(2- morpholinoethyl)carbamate 399.1/401.1 (M +H)

67

tert-Butyl 4- bromobenzyl(2- methoxyethyl)carbamate 344.1/346.1 (M + H)

68

tert-Butyl 2- bromobenzyl(2- methoxyethyl)carbamate 365.9/367.9 (M + Na)

69

1-(4-Bromobenzyl)-1H- tetrazole 238.9/240.9 (M + H)

70

tert-Butyl 4- bromobenzyl((tetrahydro furan-2- yl)methyl)carbamate370.1/372.1 (M + H)

bis-tert-Butyl 2-(3-bromobenzylamino)ethyl(methyl)carbamate (71)

To a solution of tert-butyl2-tert-butyloxycarbonylaminoethyl(methyl)carbamate (600 mg, 2.2 mmol) indry THF (5 mL) at 0° C., was added NaH (91 mg, 3.8 mmol) and thereaction was stirred for 30 minutes. 3-Bromobenzylbromide was added andthe reaction was refluxed for 3 hours, cooled to room temperature andpoured into MeOH. Solvents were removed under reduced pressure and theproduct was partitioned between EtOAc and water. Organic phase wascollected and dried over anhydrous sodium sulphate, filtered andevaporated. The crude product was purified by column chromatography onsilica gel, eluent EtOAc/hexane (1:5), to afford the title compound 71(672 mg, 80% yield) as a colourless oil. MS (m/z): 343.0/345.0 (M-Boc).

Example 59N-(3-Fluoro-4-(2-(3-((2-methoxyethylamino)methyl)phenyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(76a) Step 1. tert-Butyl2-methoxyethyl(3-(pinacolatoborolan-2-yl)benzyl)carbamate (72)

To a solution of bromide 65 (778 mg, 2.3 mmol), in dry toluene (12 mL),was added the bis(pinacolato)diboron (872 mg, 3.4 mmol), KOAc (677 mg,6.9 mmol) and Pd(PPh₃)₄ (80 mg, 69 μmol). The reaction mixture waspurged with nitrogen, refluxed for 2 hours and was allowed to cool toroom temperature. The solvent was removed under reduced pressure and theresidue was partitioned between DCM and water (30 mL/30 mL). The organicphase was collected and dried over anhydrous sodium sulphate, filteredand evaporated. The remained solid was purified by columnchromatography, eluent EtOAc/hexane (1:10) to afford title compound 72(577 mg, 64% yield) as a colorless oil. ¹H NMR (DMSO) δ (ppm): 7.54-7.52(m, 2H), 7.33-7.31 (m, 2H), 4.39 (s, 2H), 3.40-3.35 (m, 2H), 3.33-3.25(m, 2H), 3.20 (s, 3H), 1.43-1.32 (m, 9H), 1.28 (s, 12H).

Step 2. tert-Butyl3-(7-(2-fluoro-4-nitrophenoxy)thieno{3,2-b}pyridine-2-yl)benzyl(2-methoxyethyl)carbamate(73)

To a solution of the bromo-nitro compound 42 (272 mg, 0.7 mmol) in DME(4 mL), was added pinacolate 72 (578 mg, 1.5 mmol), CsF (226 mg, 2.2mmol), Pd(PPh₃)₄ (43 mg, 37 μmol) and NaHCO₃ (186 mg, 2.2 mmol)pre-dissolved in water (2 mL). The reaction mixture was purged withnitrogen, refluxed for 1 hour, cooled to room temperature and thesolvent was removed under reduced pressure. The residue was extractedwith EtOAc, the extract was dried over anhydrous sodium sulfate,filtered and concentrated to produce a brown oil which was purified bychromatography on silica gel, eluent EtOAc, to afford the title compound73 (347 mg, 85% yield) as a white solid. ¹H NMR (DMSO) δ (ppm): 8.60 (d,J=5.3 Hz, 1H), 8.47 (d-d, J=7.6 Hz, 1H), 8.19 (d, J=6.5 Hz, 1H), 8.07(s, 1H), 7.80 (d, J=7.8 Hz, 1H), 7.73-7.69 (m, 2H), 7.48 (t, J=7.8 Hz,1H), 7.30 (d, J=7.4 Hz, 1H), 6.95 (d, J=5.5 Hz, 1H), 4.48 (s, 2H), 3.21(s, 3H), 2.50 (q, J=2.2 Hz, 4H), 1.44-1.33 (m, 9H), MS (m/z): 554.0(M+H).

Step 3. tert-Butyl3-(7-(4-amino-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)benzyl(2-methoxyethyl)carbamate(74)

To a solution of 73 (347 mg, 0.6 mmol) in THF (4 mL) and MeOH (2 mL),NiCl₂ (372 mg, 1.6 mmol) was added and the solution was cooled to 0° C.NaBH₄ (95 mg, 2.5 mmol) was added portion wise. After 20 minutes, thereaction was treated with 2 M HCl and solvents were removed underreduced pressure. The concentrated mixture was basified to pH 10 withammonium hydroxide solution and the mixture was extracted with EtOAc,the extract was dried over anhydrous sodium sulfate, filtered andevaporated. The residue was purified by silica gel columnchromatography, eluent EtOAc, to afford the title compound 74 (235 mg,72% yield) as a white solid. ¹H NMR (DMSO) δ (ppm): 8.47 (d, J=5.6 Hz,1H), 7.97 (s, 1H), 7.77 (d, J=7.2 Hz, 1H), 7.70 (s, 1H), 7.48 (t, J=7.6Hz, 1H), 6.56-6.51 (m, 2H), 6.44 (dd, J=6.3 Hz, 1H), 5.54 (s, 2H), 4.84(s, 2H), 3.43 (s, 2H), 3.23 (s, 3H), 2.50 (q, J=2.2 Hz, 4H), 1.46-1.35(m, 9H).

Step 4. tert-Butyl3-(7-(2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)thieno[3,2-b]pyridin-2-yl)benzyl(2-methoxyethyl)carbamate(75)

To a solution of 74 (235 mg, 0.5 mmol) in dry THF (5 mL), 2-phenylacetylisothiocyanate (159 mg, 0.9 mmol) was added and the reaction was allowedto stir for 30 min. The solvent was removed under reduced pressure andthe resulting product was purified by chromatography on silica gel usingEtOAc/hexane (1:1) as eluting system to give the desired product (440mg, 90%) as a white solid. ¹H NMR (DMSO) δ (ppm): 8.52 (d, J=5.3 Hz,1H), 8.01 (t, J=6.5 Hz, 2H), 7.79 (d, J=7.4 Hz, 1H), 7.70 (s, 1H),7.53-7.52 (m, 2H), 7.47 (t, J=7.6 Hz, 1H), 7.34 (d, J=4.5 Hz, 4H),7.30-7.24 (m, 2H), 6.67 (d, J=5.3 Hz, 1H), 4.49 (s, 2H), 3.83 (s, 2H),3.42 (s, 2H), 3.22 (s, 3H), 2.50 (q, J=2.2 Hz, 4H), 1.45-1.33 (m, 9H).

Step 5.N-(3-Fluoro-4-(2-(3-((2-methoxyethylamino)methyl)phenyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(76a)

To a solution of 75 (440 mg, 0.6 mmol) in DCM (10 mL), TFA (145 μL, 1.9mmol) was added and the reaction was stirred for 12 hours, concentratedunder reduced pressure, and the residue was purified by silica gelcolumn chromatography, eluent MeOH/EtOAc (1:10), to afford the titlecompound 76a (227 mg, 63% yield) as a light yellow solid. ¹H NMR (DMSO)δ (ppm): 8.54 (d, J=5.5 Hz, 1H), 8.07 (s, 1H), 8.02-8.0 (m, 2H), 7.93(d-t, J=2.0 Hz, 1H), 7.55-7.53 (m, 4H), 7.34-7.32 (m, 4H), 7.29-7.26 (m,1H), 6.68 (d, J=5.3 Hz, 1H), 4.19 (s, 2H), 3.81 (s, 1H), 3.57 (t, J=4.9Hz, 2H), 3.33 (s, 2H), 3.29 (s, 3H), 3.08 (t, J=4.9 Hz, 2H), 2.84 (q,J=2.2 Hz, 4H).

Examples 60-65

Compounds 76b-g (examples 60-65) were synthesized similarly to thecompound 76a (example 59) according to the schemes 14-15, starting frombromides 66-69 and 71. Characterization of 76b-g is provided in Table8a.

TABLE 8a Characterization of compounds 76b-g(examples 60-65)

76b-g: Examples 60-65 Cpd Ex Z Chemical name Characterization 76b 60

1-(3-Fluoro-4-(2- (2-((2- methoxyethylamino) methyl)phenyl)thieno[3,2-b]pyridin-7- yloxy)phenyl)-3-(2- phenylacetyl)thiourea ¹H NMR(400 MHz,DMSO-d₆) δ ppm): 12.50(s, 1H), 11.83(s, 1H), 8.57(d, J=5.5 Hz, 1H),8.03-8.00 (m, 1H), 7.76-7.74(m, 2H), 7.61- 7.50(m, SH), 7.36-7.25(m,5H), 6.70(d, J=5.3 Hz, 1H), 4.32(s, 2H), 3.81(s, 2H), 3.52(t, J=5.1 Hz,2H), 3.16(s, 3H), 3.08(t, J= 4.7 Hz, 2H), MS(m/z): 601.0 (M + H). 76c 61

1-(3-Fluoro-4-(2- (3-((2- morpholinoethylamino) methyl)phenyl)thieno[3,2- b]pyridin-7- yloxy)phenyl)-3-(2- phenylacetyl)thiourea ¹HNMR(400 MHz, DMSO-d₆) δ (ppm): 12.49(s, 1H), 11.85(s, 1H), 8.56(d, J=5.1Hz, 1H), 8.09-7.98 (m, 5H), 7.61-7.55(m, 5H), 7.33(s, 1H), 7.27(brs,2H), 6.70(d, J=5.1 Hz, 1H), 4.30(brs, 2H), 3.82(brs, 2H), 3.73(brs, 4H),MS(m/z) 656.2(M + H). 76d 62

N-(3-Fluoro-4-(2- (4-((2- (methylamino)ethyl amino)methyl)phenyl)thieno[3,2- b]pyridin-7- yloxy)phenylcarbamo- thioyl)-2- phenylacetamide¹H NMR(DMSO): 12.49(s, 1H), 11.84(s, 1H), 8.51(d, J=5.5 Hz),8.04-7.99(m, 2H), 7.87(d, J=7.6 Hz, 2H), 7.54-7.53(m, 2H), 7.34- 7.33(m,5H), 7.29-7.22(m, 2H), 6.64(d, J=5.5 Hz, 1H), 4.42-4.39 (m, 2H), 3.82(s,2H), 3.29(brs, 2H), 3.23(brs, 3H), 2.78-2.76(m, 2H), MS: calcd 599.74,found 800.1 (M + H). 76e 63

1-(3-Fluoro-4-(2- (4-((2- methoxyethylamino) methyl)phenyl)thieno[3,2-b]pyridin-7- yloxy)phenyl)-3-(2- phenylacetyl)thiourea ¹HNMR(400 MHz, DMSO-d₆) δ ppm): 12.48(s, 1H), 11.83(s, 1H), 9.02(s, 2H),8.54(d, J=5.5 Hz, 1H), 8.13(s, 1H), 8.02(d, J=13.3 Hz, 1H), 7.97(d,J=8.2 Hz, 2H), 7.53(m, 2H), 7.33(m, 4H), 7.28 (m, 2H), 6.67(d, J=5.5 Hz,1H), 4.22(m, 2H), 3.83(s, 2H), 3.59(t, J= 4.9 Hz, 2H), 3.31(s, 3H), 3.12(m, 2H), MS(m/z): 601.2(M + H). 76f 64

1-(3-Fluoro-4-(2- (3-((2- (methylamino)ethyl amino)methyl)phenyl)thieno[3,2- b]pyridin-7- yloxy)phenyl)-3-(2- phenylacetyl)thiourea ¹HNMR(DMSO) δ(ppm): 12.49 (s, 1H), 11.85(s, 1H), 8.55(d, J= 5.09 Hz, 1H),8.08(s, 1H), 8.04 (brs, 1H), 8.00-7.97(m, 2H), 7.62- 7.53(m, 4H),7.36-7.32(m, 4H), 7.29-7.26(m, 1H), 6.69(d, J=5.5 Hz, 1H), 4.31(brs,2H), 3.82(s, 2H), 3.31-3.27(m, 4H), 2.63(s, 3H), MS(m/z) 600.2(M + H).76g 65

1-(4-(2-(4-((1H- Tetrazol-1- yl)methyl)phenyl) thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenyl)-3-(2- phenylacetyl)thiourea ¹H NMR(DMSO)δ(ppm): 12.46 (s, 1H), 11.82(s, 1H), 9.54(s, 1H), 8.51(dd, J=1.1 and5.09 Hz, 1H), 8.1(s, 1H), 7.96(d, J=23.3 Hz, 1H), 7.90(d, J=6.7 Hz, 2H),7.53 (m, 2H), 7.43(d, J=8.6 Hz, 2H), 7.32(m, 4H), 7.26(m, 1H), 6.65(d,J=5.5 Hz, 1H), 5.78(s, 2H), 3.82 (s, 2H). MS(m/z) 596.1 (M + H).

Example 661-(3-Fluoro-4-(2-(4-(((tetrahydrofuran-2-yl)methylamino)methyl)phenyl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-3-(2-phenylacetyl)thiourea(81) Step 1.tert-Butyl(4-(7-chlorothieno[3,2-b]pyridin-2-yl)phenyl)methyl((tetrahydrofuran-2-yl)methyl)carbamate(77)

To a solution of the trimethyltin compound 9 (1.4 g, 3.06 mmol) (scheme2) and bromide 70 (2.25 g, 6.11 mmol) (scheme 14, Table 8) in drytoluene (50 ml) was added Pd(PPh₃)₄ (176 mg, 0.153 mmol). The reactionmixture was refluxed overnight, cooled to room temperature and thesolvents were removed under reduced pressure. The resultant solid wastriturated with hexane/ether and then purified by column chromatography,eluents EtOAc/Hexane 1:9, then EtOAc:hexane 4:6, to afford titlecompound 77 as a white solid (1.2 g, 86% yield). MS (m/z): 459.2/461.2(M+H).

Step 2. tert-Butyl(4-(7-(2-fluoro-4-nitrophenoxy)thieno[3,2-b]pyridin-2-yl)phenyl)methyl((tetrahydrofuran-2-yl)methyl)carbamate(78)

To a solution of 77 (1.0 g, 2.18 mmol) in Ph₂O (10 ml) was added2-fluoro-4-nitrophenol (856 mg, 5.45 mmol) and potassium carbonate (904mg, 6.55 mmol). The reaction mixture was heated at 180° C. for 4 hrs,cooled to room temperature, diluted with DCM, filtered and concentrated.The residue was purified by column chromatography, eluent EtOAc:hexane8:2, to afford title compound 78 (250 mg, 20% yield). MS (m/z): 580.3(M+H).

Steps 3-4. tert-Butyl(4-(7-(2-Fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)thieno[3,2-b]pyridin-2-yl)phenyl)methyl((tetrahydrofuran-2-yl)methyl)carbamate(80)

To a solution of 78 (250 mg, 0.431 mmol) in MeOH (10 mL) at 0° C. wasadded NiCl₂×6H₂O (205 mg, 0.86 mmol) and NaBH₄ (64 mg, 1.72 mmol). Thereaction mixture was allowed to stir for 1 hr, concentrated to drynessand the resultant solid was dissolved in 2 M HCl. This solution was thenmade basic with concentrated aqueous ammonium hydroxide and extractedwith DCM. The DCM extract was dried over anhydrous sodium sulfate,filtered and evaporated to form the amine 79 (236 mg, 100% yield), whichwas used without characterization and further purification.

To a solution of the amine 79 (236 mg, 0.43 mmol) in THF (10 mL) wasadded 2-phenylacetyl isothiocyanate (114 mg, 6.44 mmol). The reactionmixture was stirred for 1 hr, concentrated and the residue was purifiedby column chromatography, eluent—gradient from EtOAc:hexane 1:1 toEtOAc, to afford title compound 80 (200 mg, 64% yield) as a white solid.MS (m/z): 725.5 (M+H).

Step5.1-(3-Fluoro-4-(2-(4-(((tetrahydrofuran-2-yl)methylamino)methyl)phenyl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-3-(2-phenylacetyl)thiourea(81)

To a solution of 80 (200 mg, 0.28 mmol) in toluene (5 mL), TFA (excess)was added. The reaction mixture was allowed to stir overnight, thesolvent was removed under reduced pressure and the remained solid wastriturated with diethyl ether to afford title compound 81 as the di-TFAsalt (130 mg, 57% yield). ¹H NMR (DMSO) δ (ppm): 12.47 (s, 1H), 11.83(s, 1H), 9.06 (s, 2H), 8.53 (dd, J=2.0 and 5.5 Hz, 1H), 8.13 (s, 1H),8.0 (d, J=12.1 Hz, 1H), 7.97 (d, J=8.7 Hz, 2H), 7.63 (d, J=8.2 Hz, 2H),7.53 (m, 2H), 7.32 (m, 4H), 7.27 (m, 1H), 6.68 (d, J=5.8 Hz, 1H), 4.23(m, 1H), 3.82 (s, 2H), 3.78 (m, 1H), 3.71 (m, 1H), 3.11 (m, 1H), 2.95(m, 1H), 2.0 (m, 1H), 1.98 (m, 2H), 1.56 (m, 1H). MS (m/z) 627.3 (M+H).

Example 677-[2-Fluoro-4-(3-phenylacetyl-thioureido)-phenoxy]-thieno[3,2-b]pyridine-2-sulfonicacid methoxy-methyl-amide (85) Step 1.7-Chloro-N-methoxy-N-methylthieno[3,2-b]pyridine-2-sulfonamide (82)

To a solution of chloride 2 (scheme 1) (700 mg, 4.14 mmol) in THF (20ml) was added n-BuLi (2 ml, 4.97 mmol, 2.5 M solution in hexanes) at−78° C. and the reaction mixture was stirred for 20 mins. SO₂-gas waspassed over the surface of the solution for 3 hrs at the sametemperature, then for an additional hr at 0° C. The reaction mixture wasevaporated. DCM (20 ml) and NCS (605 mg, 4.55 mmol) were added and thereaction mixture was stirred at room temperature for 1.5 hrs, filteredthrough a celite pad and concentrated to produce a pink solid. The solidwas dissolved in acetone (20 ml); MeNH(OMe) hydrochloride (608 mg, 6.21mmol) and triethylamine (627 mg, 6.21 mmol) were added and the reactionmixture was stirred at room temperature overnight. The solvent wasremoved under reduced pressure and the residue was dissolved in EtOAc.The EtOAc solution was washed with water, dried over anhydrous sodiumsulfate, filtered and evaporated. The residue was purified by columnchromatography (eluent EtOAc:hexane, 1:1) to afford the title compound82 (485 mg, 40% yield) as a pink solid. MS (m/z) 561.1 (M+H).

Step 2.7-(2-Fluoro-4-nitrophenoxy)-N-methoxy-N-methylthieno[3,2-b]pyridine-2-sulfonamide(83)

A mixture of 82 (400 mg, 1.37 mmol), 2-fluoro-4-nitrophenol (321 mg,2.05 mmol) and K₂CO₃ (756 mg, 5.48 mmol) were heated to 190° C. indiphenyl ether (55 ml) for 3 hrs. The mixture was cooled to roomtemperature, diluted with DCM and filtered. The filtrate wasconcentrated and purified by column chromatography (eluent EtOAc:hexane,1:1) to afford title compound 83 (225 mg, 40% yield). MS (m/z) 414.0(M+H).

Steps 3-4.7-[2-Fluoro-4-(3-phenylacetyl-thioureido)-phenoxy]-thieno[3,2-b]pyridine-2-sulfonicacid methoxy-methyl-amide (85)

To a solution of the nitro compound 83 (225 mg, 0.54 mmol) in THF (5 ml)and water (2 ml) was added SnCl₂×2H₂O (742 mg, 3.3 mmol). The reactionmixture was refluxed for 3 hrs, diluted with EtOAc and washed withaqueous ammonium hydroxide. The washings were combined and extractedwith DCM. Both EtOAc- and DCM-phases were combined, dried over anhydroussodium sulfate, filtered and evaporated to produce the amine 84 (168 mg,81% yield), which was used without characterization and furtherpurification.

To a solution of the amine 84 (225 mg, 0.59 mmol) in THF (8 ml) wasadded phenyl-acetyl isothiocyanate (208 mg, 1.18 mmol). The reactionmixture was stirred for 1 hr, concentrated under reduced pressure andpurified by column chromatography (eluent EtOAc) to afford 85 (323 mg,98% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.52(s, 1H), 11.86 (s, 1H), 8.74 (d, J=5.3 Hz, 1H), 8.33 (s, 1H), 8.07 (d,J=13.5 Hz, 1H), 7.61 (m, 2H), 7.36 (m, 4H), 7.29 (m, 1H), 3.86 (s, 3H),3.84 (s, 2H), 2.96 (s, 3H). MS (m/z): 561.3 (M+H).

Example 687-[2-Fluoro-4-(3-phenylacetyl-thioureido)-phenoxy]-thieno[3,2-b]pyridine-2-sulfonicacid amide (86)

Title compound 86 was obtained following the procedures described forthe compound 85 (example 67, scheme 16) but substituting in the firststep O-methyl hydroxylamine for ammonia. ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 13.82 (s, 1H), 13.15 (s, 1H), 9.98 (m, 1H), 9.4-9.2 (m, 4H), 8.87(s, 2H), 8.64 (m, 5H), 8.15 (s, 1H), 3.82 (s, 2H). MS (m/z): 517.3(M+H).

Example 691-(4-(2-(1-Ethyl-5-methyl-1H-imidazol-4-yl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenyl)-3-(2-(2-methoxyphenyl)acetyl)thiourea(90) Step 1.7-Chloro-2-(1-ethyl-5-methyl-1H-imidazol-4-yl)-thieno[3,2-b]pyridine(87)

To a solution of 2 (1.14 g, 6.76 mmol) in THF (60 ml) was added, at −78°C., n-BuLi (3.38 ml, 2.5 M soln in hexanes) and the reaction mixture wasstirred at the same temperature for 10 min. A solution of ZnCl₂ (16.9ml, 2.5 ml, 0.5M in THF) was added and the reaction mixture was warmedto room temperature. Then a solution of1-ethyl-4-iodo-5-methyl-1H-imidazole (800 mg, 3.38 mmol) (Pyne, S. G andCliff, M. D. Synthesis 1994, 681) and Pd(PPh₃)₄ (390 mg, 0.34 mmol) inTHF (15 ml) were added and the reaction mixture was refluxed for 3 hrs,cooled to room temperature, quenched with conc. ammonium hydroxidesolution and made neutral with concentrated aqueous HCl. The neutralsolution was extracted with EtOAc, the extract was collected, dried overanhydrous sodium sulfate, and filtered. The filtrate was evaporated andthe residue was purified by column chromatography (eluent MeOH:EtOAc,1:9) to afford the title compound 87 (1.1 g, 100% yield) as a brown oil.MS (m/z) 278.0/280.0 (M+H).

Step 2.2-(1-Ethyl-5-methyl-1H-imidazol-4-yl)-7-(2-fluoro-4-nitro-phenoxy)-thieno[3,2-b]pyridine(88)

A suspension of 87 (650 mg, 2.35 mmol), potassium carbonate (970 mg,7.04 mmol) and 2-fluoro-4-nitrophenol (738 mg, 4.7 mmol) were heated at190° C. in diphenyl ether (15 ml) for 3 hrs. The mixture was cooled toroom temperature, diluted with DCM and filtered. The filtrate wasconcentrated and the residue was purified by column chromatography(eluents EtOAc, then MeOH:EtOAc, 1:9) to afford title compound 88 (600mg, 64%) as a yellow solid. MS (m/z) 399.0 (M+H).

Steps 3-4.1-(4-(2-(1-Ethyl-5-methyl-1H-imidazol-4-yl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenyl)-3-(2-(2-methoxyphenyl)acetyl)thiourea(90)

To a solution of 88 (200 mg, 0.5 mmol) in MeOH (8 ml) and THF (2 ml) at0° C. was added NiCl₂×6H₂O (237 mg, 1 mmol) and NaBH₄ (74 mg, 2 mmol).The reaction mixture was allowed to stir for 1 hr, concentrated todryness and the resultant solid was dissolved in 1 M HCl. The acidicsolution was then made basic with concentrated aqueous ammoniumhydroxide and extracted with EtOAc. The organic phase was collected,dried over anhydrous sodium sulfate and filtered. The solvent wasevaporated under reduced pressure and the residue was triturated withEt₂O to afford the crude amine 89 (184 mg, 100% yield) which was usedimmediately in the next step [without characterization].

To a solution of the amine 89 (180 mg, 0.49 mmol) in THF (10 ml) wasadded (2-methoxy-phenyl)-acetyl isothiocyanate (200 mg, 0.98 mmol). Thereaction mixture was stirred for 10 min, concentrated and the residuewas purified by column chromatography (eluents EtOAc, then toMeOH-EtOAc, 1:9), to afford title compound 90 (84 mg, 30% yield) asyellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm) 12.56 (s, 1H), 11.73 (s,1H), 8.43 (d, J=5.5 Hz, 1H), 8.04 (d, J=12.3 Hz, 1H), 7.71 (s, 1H), 7.51(m, 4H), 7.25 (m, 2H), 6.97 (d, J=8.2 Hz, 1H), 6.92 (t, J=7.2 Hz, 1H),6.97 (d, J=8.2 Hz, 1H), 6.92 (t, J=7.2 Hz, 1H), 6.56 (d, J=5.5 Hz, 1H),4.0 (q, J=3.2 Hz, 2H), 3.80 (s, 2H), 3.77 (s, 3H), 2.47 (s, 3H), 1.31(t, J=3.2 Hz, 2H). MS (m/z) 576.1 (M+H).

Example 70N-(3-Fluoro-4-(2-(1-(2-methoxyethyl)-1H-imidazol-4-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-(2-methoxyphenyl)acetamide(96) Step 1.7-Chloro-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)thieno[3,2-b]pyridine(91)

To a solution of 2 (9.4 g, 56.0 mmol) in THF (150 ml) at −78° C. wasadded n-BuLi (28 ml, 70.0 mmol, 2.5 M soln in hexanes) and the reactionmixture was stirred at −78° C. for 45 mins. A solution of ZnCl₂ (140 ml,70.0 mmol, 0.5M in THF) was added and the reaction mixture was warmed toroom temperature. To the warmed mixture a solution of4-iodo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole [Carl J. Loveyet al, Tetrahedron Lett., 2004, 45(28) 5529-5532] (9.0 g, 28.0 mmol) andPd(PPh₃)₄ (2.5 g, 2.1 mmol) in THF (50 ml) were added. The reactionmixture was heated to reflux for 3 hrs, cooled to room temperature,quenched with aqueous ammonium hydroxide and made neutral with aqueousHCl. The neutral solution was extracted with EtOAc, the organic phasewas collected, dried over anhydrous sodium sulfate and filtered. Thefiltrate was evaporated under reduced pressure and the residue waspurified by column chromatography (eluent MeOH-EtOAc, 1:20) to affordthe title compound 91 (7.5 g, 73% yield) as a brown oil. MS (m/z)366.0/368.0 (M+H).

Step 2.7-(2-Fluoro-4-nitrophenoxy)-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)thieno[3,2-b]pyridine(92)

A suspension of 91 (4.2 g, 11.5 mmol), potassium carbonate (7.95 g, 57.5mmol) and 2-fluoro-4-nitrophenol (4.97 g, 31.6 mmol) was heated at 190°C. in diphenyl ether (15 ml) for 4.5 hrs, cooled to room temperature,diluted with DCM and filtered. The filtrate was concentrated underreduced pressure and purified by column chromatography (eluents hexaneand acetone/hexane, 45:55) to afford title compound 92 (3.4 mg, 61%yield) as a yellow solid MS (m/z) 487.0 (M+H).

Step 3.7-(2-Fluoro-4-nitrophenoxy)-2-(1H-imidazol-4-yl)thieno[3,2-b]pyridine(93)

To a suspension of 92 (3.3 g, 6.8 mmol) in EtOH (8 ml) was addedconcentrated HCl (7 ml) and distilled water (4 ml). The mixture washeated at 80-90° C. for 2.5 h, cooled to room temperature andconcentrated under reduced pressure. The remaining residue was subjectedto azeotropic distillation with EtOH followed by neutralization withsaturated aqueous NaHCO₃. The solid that precipitated was filtered andwashed with water, and the filtrate was extracted with EtOAc. The solidand EtOAc extract were combined, evaporated under reduced pressure andthe residue was collected and dried to afford the title compound 93 (2.4g, 100% yield) as a yellow solid. MS (m/z) 357.0 (M+H).

Step 4.7-(2-Fluoro-4-nitrophenoxy)-2-(1-(2-methoxyethyl)-1H-imidazol-4-yl)thieno[3,2-b]pyridine(94)

To a solution of 93 (300 mg, 0.84 mmol) in dry DMF (3 ml) at 0° C. wasadded NaH (40 mg, 60% dispersion in oil, 1.0 mmol). The mixture wasallowed to warm to room temperature over 0.5 h then re-cooled to 0° C.Bromoethylmethyl ether (123 mg, 0.88 mmol) was added and mixture wasallowed to warm to room temperature over 20 hours, concentrated andpartitioned between EtOAc and water. The EtOAc phase was dried overanhydrous Na₂SO₄, filtered, concentrated and purified by columnchromatography (eluents hexane and acetone/hexane 75:25) to afford thetitle compound 94 (126 mg, 36% yield) as a pale yellow solid. MS (m/z)415.1.0 (M+H).

Step 5.3-Fluoro-4-(2-(1-(2-methoxyethyl)-1H-imidazol-4-yl)thieno[3,2-b]pyridin-7-yloxy)benzenamine(95)

Following the procedure described above for compound 89 (scheme 17) butreplacing the nitro compound 88 with the nitro compound 94, titlecompound 95 was obtained as a beige solid (23 mg, 100% yield). MS (m/z)385.2 (M+H).

Step 6.N-(3-Fluoro-4-(2-(1-(2-methoxyethyl)-1H-imidazol-4-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-(2-methoxyphenyl)acetamide(96)

Following the procedure described above for the compound 90 (scheme 17)but replacing the amine 89 with the amine 95 and using2-(2-methoxyphenyl)acetyl isothiocyanate instead of 2-phenylacetylisothiocyanate, title compound 96 was obtained as a beige solid (6 mg,17% yield). ¹H NMR (400 MHz, DMSO-d₆) δ (ppm) 12.57 (1H, s), 11.77 (1H,s), 8.53 (1H, d, J=5.48 Hz), 8.08 (1H, d, J=12.03 Hz), 8.02 (1H, s),7.91 (1H, s), 7.76 (1H, s), 7.59-7.52 (2H, m), 7.28-7.21 (2H, m), 6.98(1H, d, J=8.22 Hz), 6.91 (1H, d, J=7.44 Hz), 6.71 (1H, d, J=5.67 Hz),4.21 (2H, t, J=4.89 Hz), 3.80 (2H, s), 3.77 (3H, s), 3.65 (2H, t, J=4.89Hz), 3.26 (3H, s). MS (m/z) 592.1 (M+H).

Example 71(S)—N-(3-Fluoro-4-(2-(4-((3-hydroxypyrrolidin-1-yl)methyl)phenyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(104) Step 1. (S)-1-(4-Bromobenzyl)pyrrolidin-3-ol (97)

Title compound 97 was obtained, according to the scheme 14 by reacting(S)-pyrrolidin-3-ol with 3-bromobenzylbromide, as a white solid (1.3 g63% yield). LRMS 256.1/258.1 (M+1).

Step 2. 7-Chloro-2-(tributylstannyl)thieno[3,2-b]pyridine (98)

To a solution of the chloride 2 (18.72 g, 110 mmol) in THF (200 mL) at−78° C. n-BuLi (51 mL, 127 mmol) was added and the reaction mixture wasstirred for about 30 minutes. The tributylchlorostannane (25.4 mL, 93mmol) was added and the mixture was stirred at −78° C. for another 60minutes, quenched with water [at the same temperature] and allowed towarm up to room temperature. The warmed mixture was extracted withEtOAc, the extract was dried over anhydrous sodium sulfate, filtered andevaporated under reduced pressure. The residue was purified by flashchromatography, eluents EtOAc-hexane (15:85), then EtOAc-hexane (25:75)to afford title compound 98 (30.2 g, 77% yield) as a yellow oil. LRMS(M+1) 459.1 (100%).

Step 3.(S)-1-(4-(7-Chlorothieno[3,2-b]pyridin-2-yl)benzyl)pyrrolidin-3-ol (99)

To a solution of 98 (2.44 g, 5.30 mmol) and bromide 97 (1.3 g, 5.07mmol) in dry toluene (30 mL) was added Pd(PPh₃)₄ (290 mg, 0.25 mmol).The reaction mixture was heated to reflux for 1.5 h, cooled to roomtemperature and the solvent was removed under reduced pressure. Theresultant solid was purified by column chromatography, eluentsEtOAc-Hexane (1:1) then MeOH/EtOAc (20:80), to afford title compound 99(1.24 g, 71% yield) as a white solid. MS (m/z): 345.1/347.1 (M+H).

Step 4.(S)-2-(4-((3-(tert-Butyldimethylsilyloxy)pyrrolidin-1-yl)methyl)phenyl)-7-chlorothieno[3,2-b]pyridine(100)

To a suspension of 99 (0.5 g, 1.45 mmol) in dry THF (7 ml) at 0° C. wasadded TBDMSOTf (0.5 ml, 2.2 mmol) and the reaction mixture was stirredfor 20 min. Et₃N (0.61 ml, 4.4 mmol) was added and mixture was stirredat the same conditions for another hour, quenched by the addition ofwater (˜2 ml) and concentrated to dryness. The remained solid waspartitioned between EtOAc and water. Organic phase was collected, washedwith brine, dried over anhydrous Na₂SO₄ and concentrated. The residuewas purified by column chromatography, eluents EtOAc/hexane (1:1) thenMeOH/EtOAc (5:95) to afford title compound 100 (637 mg, 96% yield) as awhite solid. MS (m/z): 459.2/461.2 (M+H).

Step 5.(S)-2-(4-((3-(tert-Butyldimethylsilyloxy)pyrrolidin-1-yl)methyl)phenyl)-7-(2-fluoro-4-nitrophenoxy)thieno[3,2-b]pyridine(101)

To a solution of 100 (250.0 mg, 0.54 mmol) in Ph₂O (4 ml) was added2-fluoro-4-nitrophenol (171 mg, 1.1 mmol) and potassium carbonate (304mg, 2.2 mmol). The reaction mixture was heated to 195° C. for 3 hrs,cooled to room temperature, diluted with DCM, filtered and concentrated.The residue was purified by column chromatography, eluents EtOAc, thenMeOH/EtOAc (20-80), to afford title compound 101 (94 mg, 30% yield) as awhite solid. MS (m/z): 580.3 (M+H).

Step 6.(S)—N-(4-(2-(4-((3-(tert-Butyldimethylsilyloxy)pyrrolidin-1-yl)methyl)phenyl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenylcarbamothioyl)-2-phenylacetamide(103)

To a solution of the nitro compound 101 (90 mg, 0.16 mmol) in MeOH (4ml) at 0° C. was added NiCl₂×6H₂O (74 mg, 0.31 mmol) and NaBH₄ (23 mg,0.62 mmol). The reaction mixture was allowed to stir for 1 hr,concentrated to dryness and the resultant solid was dissolved in 2 MHCl. The acidic solution was then made basic with aqueous ammoniumhydroxide solution and extracted with EtOAc. The organic extract wasdried over anhydrous sodium sulfate, filtered and evaporated to form theamine 102 (80 mg, 95% yield), which was used without furtherpurification and characterization.

To a solution of the amine 102 (80 mg, 0.15 mmol) in THF (2 mL) wasadded 2-phenylacetyl isothiocyanate (64 mg, 0.36 mmol). The reactionmixture was stirred for 1 hr, concentrated and the residue was purifiedby column chromatography, eluents EtOAc:hexane (1:1), then EtOAc, toafford title compound 103 (34 mg, 30% yield) as a white solid. MS (m/z):727.5 (M+H).

Step 7.(S)—N-(3-fluoro-4-(2-(4-((3-hydroxypyrrolidin-1-yl)methyl)phenyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(104)

To a solution of 103 (34 mg, 0.047 mmol) in CH₃CN/MeOH (0.5 mL/2.0 mL),concentrated HCl (8 drops) was added and the reaction was allowed tostir 2 h. The solvents were removed under reduced pressure and theresultant solid was triturated with diethyl ether followed bypurification by Gilson HPLC preparative system, column Aquasil C18 (25%MeOH in water to 100% MeOH), to afford title compound 104 (2.5 mg, 9%yield), as a white solid. ¹H NMR (DMSO) δ (ppm): 11.82 (1H, s), 8.51(1H, d, J=5.28 Hz), 8.23 (1H, s), 8.02-7.98 (2H, m), 7.82 (2H, d, J=7.83Hz), 7.52 (2H, br), 7.41 (2H, d, J=7.83 Hz), 7.33-7.25 (5H, m), 6.64(1H, d, J=5.09 Hz), 4.20 (1H, br), 3.83 (2H, s), 3.38 (2H, s), 2.34-2.32(2H, m), 2.03-1.96 (2H, m), 1.56 (2H, br). MS (m/z) 613.3 (M+H).

Example 72(S)-1-(4-(7-(2-Fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)thieno[3,2-b]pyridin-2-yl)benzyl)pyrrolidine-2-carboxylicacid (106)

Step 1. (S)-tert-Butyl 1-(4-bromobenzyl)pyrrolidine-2-carboxylate (105)

Title compound 105 was obtained, according to the scheme 14 by reacting(S)-tert-butyl pyrrolidine-2-carboxylate with 3-bromobenzylbromide, as awhite solid (1.62 g, 94% yield). LRMS 340.1/342.1 (M+1).

(S)-1-(4-(7-(2-Fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)thieno[3,2-b]pyridin-2-yl)benzyl)pyrrolidine-2-carboxylicacid (106)

Title compound 106 was obtained following the procedures similar to theones described above for the synthesis of compound 104 (example 71,scheme 19), replacing bromide 97 with the bromide 105 in the secondstep, skipping the step 4 (TBS-protection) and using in the last stepTFA/DCM mixture for tert-butyl ester de-protection. ¹H NMR (400 MHz,DMSO-d₆): δ12.47 (1H, s), 11.82 (1H, s), 8.53 (1H, br), 8.13 (1H, s),8.01 (1H, d, J=12.91 Hz), 7.96 (2H, d, J=7.02 Hz), 7.60 (2H, d, J=7.63Hz), 7.54 (2H, br), 7.34-7.27 (5H, m), 6.67 (1H, d, J=5.09 Hz), 4.40(1H, br), 4.23 (1H, br), 3.83 (2H, s), 3.38 (2H, s), 2.38 (1H, br), 2.00(2H, br), 1.85 (1H, br). MS (m/z) 641.3 (M+H).

Examples 73-82 Compounds 13i-13r

Following the procedures described above for the synthesis of compound13a (example 12, scheme 2) but substituting trimethyltin chloride in thestep 1 for tributyltin chloride and 2-bromothiazole in the step 2 forheteroaryl bromides shown in the Table 9, title compounds 13i-13r weresynthesized. Characterization of compounds 13i-13r (examples 73-82) isprovided in the Table 10.

TABLE 9 Heteroaryl bromides used in the synthesis of compounds13i-13r(examples 73-82) Heteroaryl bromide Preparation

McCullum, P., et al., Aust. J. Chem. 52(3), 1999, 159-166

McCullum, P., et al., Aust. J. Chem. 52(3), 1999, 159-166

Borai, M. El et al. Pol J. Chem. 55, 1981, 1659

a)Begtrup, M.; Larsen, P.; Acta Chem. Scand. 44, 10; 1990; 1050-1057. b)Begtrup, M.; Bull. Soc. Chim. Belg.; 97; 8-9; 1988; 573-598. c) Begtrup,M.; Larsen, P.; Chem. Pharm. Bull. 42, 9; 1994; 1784-& 1790.

a)Begtrup, M.; Larsen, P.; Acta Chem. Scand. 44, 10; 1990; 1050-1057. b)Begtrup, M.; Bull. Soc. Chim. Belg.; 97; 8-9; 1988; 573-598. c) Begtrup,M.; Larsen, P.; Chem. Pharm. Bull. 42, 9; 1994; 1784-& 1790.

a) Begtrup, M.; Larsen, P.; Acta Chem. Scand. 44, 10; 1990; b) Begtrup,M.; Bull. Soc. Chim. Belg.; 97; 8-9; 1988; 573-598. c) Begtrup, M.;Larsen, P.; Chem. Pharm. Bull. 42, 9; 1994; 1784-& 1790.

a) Begtrup, M.; Larsen, P.; Acta Chem. Scand. 44, 10; 1990; 1050-1057.b) Begtrup, M.; Bull. Soc. Chim. Belg.; 97; 8-9; 1988; 573-598. c)Begtrup, M.; Larsen, P.; Chem. Pharm. Bull. 42, 9; 1994; 1784-& 1790. d)Reference where BrCN is being used for such a purpose

a) Begtrup, M.; Larsen, P.; Acta Chem. Scand. 44, 10; 1990; 1050-1057.b) Begtrup, M.; Bull. Soc. Chim. Belg.; 97; 8-9; 1988; 573-598. c)Begtrup, M.; Larsen, P.; Chem. Pharm. Bull. 42, 9; 1994; 1784-& 1790.

a) Begtrup, M.; Larsen, P.; Acta Chem. Scand. 44, 10; 1990; 1050-1057.b) Begtrup, M.; Bull. Soc. Chim. Belg.; 97; 8-9; 1988; 573-598. c)Begtrup, M.; Larsen, P.; Chem. Pharm. Bull. 42, 9; 1994; 1784-& 1790.

A commercial product

A commercial product

TABLE 10 Characterization of compounds 13i-13r(examples 73-82)

13i-13r: Examples 73-82 Cpd Ex R Name Characterization 13i 73

N-(4-(2-(1-Ethyl-1H- imidazol-2- yl)thieno[3,2- b]pyridin-7-yloxy)-3-fluorophenylcarbamo thioyl)-2- phenylacetamide ¹H NMR(400 MHz, DMSO-d₆)δ ppm 12.48(1H, s), 11.81(1H, s), 8.52(1H, d, J=5.09 Hz), 8.02 (1H, d,J=12.13 Hz), 7.82(1H, s), 7.53-7.46(3H, m), 7.34-7.28(5H, m), 7.06(1H,s), 6.68(1H, d, J=5.48 Hz), 4.37(2H, q, J=6.85 Hz), 3.83(2H, s),1.43(3H, t, J=7.24 Hz) MS(m/z) 532.3 (M + H) 13j 74

N-(3-Fluoro-4-(2-(1- isopropyl-1H- imidazol-2- yl)thieno[3,2-b]pyridin-7- yloxy)phenylcarbamo thioyl)-2- phenylacetamide ¹H NMR(400MHz,DMSO-d₆) δ ppm 12.48(1H, s), 11.82(1H, s), 8.53(1H, d, J=5.38 Hz),8.02 (1H, d, J=12.13 Hz), 7.81(1H, s), 7.60(1H, s), 7.53(2H, d, J=5.28Hz), 7.34-7.26(5H, m), 7.09(1H, s), 6.68(1H, d, J=5.28 Hz), 4.98 (1H,quintet, J=6.46 Hz), 3.83 (2H, s), 1.49(6H, d, J=6.46 Hz) MS(m/z)546.3(M + H) 13k 75

N-(3-Fluoro-4-(2-(4- methyl-4H-1,2,4- triazol-3- yl)thieno[3,2-b]pyridin-7- yloxy)phenylcarbamo thioyl)-2- phenylacetamide ¹H NMR(400MHz, DMSO-d₆) δ ppm 12.45(1H, s), 11.78(1H, s), 8.56(1H, d, J=5.28 Hz),8.16(1H, s), 8.02(s, 1H), 7.98(1H, s), 7.52 (2H, s), 7.30-7.21(5H, m),6.72 (1H, d, J=5.09), 4.16(3H, s), 3.78 (2H, s). MS(m/z) 519.2(M + H)13l 76

N-(3-Fluoro-4-(2-(1- methyl-1H-imidazol- 4-yl)thieno[3,2- b]pyridin-7-yloxy)phenylcarbamo thioyl)-2- phenylacetamide ¹H NMR(400 MHz,DMSO-d₆) δppm 44(1H, d, J=5.67 Hz), 8.01 (1H, d, J=12.13 Hz), 7.85(1H, s),7.71(1H, s), 7.68(1H, s), 7.51-7.50 (2H, m), 7.33-7.27(5H, m), 6.57 (1H,d, J=5.48 Hz), 3.83(2H, s), 3.72(3H, s). MS(m/z) 518.2 (M + H) 13m 77

N-(4-(2-(1-Ethyl-1H- imidazol-4- yl)thieno[3,2- b]pyridin-7-yloxy)-3-fluorophenylcarbamo thioyl)-2- phenylacetamide ¹H NMR(400 MHz,DMSO-d₆) δppm 12.50(1H, s), 11.84(1H, s), 8.56(1H, d, J=5.87 Hz), 8.14 (1H, s),8.11-8.04(2H, m), 7.78 (1H, s), 7.57-7.56(2H, m), 7.35- 7.56(5H, m),6.76(1H, d, J=5.48 Hz), 4.10(2H, q, J=7.24 Hz), 3.84(2H, s), 1.44(3H, t,J=7.24 Hz). MS(m/z) 532.2(M + H) 13n 78

N-(3-Fluoro-4-(2-(1- (2-morpholinoethyl)- 1H-imidazol-2- yl)thieno[3,2-b]pyridin-7- yloxy)phenylcarbamo thioyl)-2- phenylacetamide ¹H NMR(400MHz,DMSO-d₆) δ ppm 12.49(1H, s), 11.82(1H, s), 8.52(1H, d, J=5.09 Hz),8.02 (1H, d, J=11.93 Hz), 7.90(1H, s), 7.54-7.48(3H, m), 7.33-7.24(5H,m), 7.06(1H, s), 6.69(1H, d, J=4.90 Hz), 4.44(2H, s), 3.83 (2H, s),3.55-3.51(4H, m), 2.71 (2H, s), 2.50(2H, s) . MS(m/z) 617.3(M + H) 13o79

N-(3-Fluoro-4-(2-(1- (2-morpholinoethyl)- 1H-pyrazol-4- yl)thieno[3,2-b]pyridin-7- loxy)phenylcarbamo thioyl)-2- phenylacetamide ¹H NMR(DMSO)δ(ppm): 12.46 (1H, s), 11.81(1H, s), 8.45(1H, d, J=5.48 Hz), 8.33(1H,s), 8.01-7.99 (2H, m), 7.69(1H, s), 7.51-7.49 (2H, m), 7.34-7.24(5H, m),6.59 (1H, d, J=5.48 Hz), 4.26(2H, t, J=6.46 Hz), 3.82(2H, s), 3.54(4H,t, J=4.40 Hz), 2.74(2H, t, J=6.46 Hz), 2.42 (4H, br). MS(m/z) 617.3 (M +H). 13p 80

N-(4-(2-(1-Ethyl-1H- pyrazol-4- yl)thieno[3,2- b]pyridin-7-yloxy)-3-fluorophenylcarbamo thioyl)-2- phenylacetamide ¹H NMR(400 MHz, DMSO-d₆)δ ppm: 12.49(s, 1H), 11.84(s, 1H), 8.47(d, J=5.6 Hz, 1H), 8.36(s, 1H),8.02-7.99(m, 2H), 7.70(s, 1H), 7.58-7.51(m, 2H), 7.39-7.32(m, 4H),7.31-7.25(m, 1H), 6.60(d, J= 5.6 Hz, 1H), 4.18(q, J=7.2 Hz, 2H), 3.83(s,2H), 1.41(t, J=7.2 Hz, 3H). 13q 81

N-(3-Fluoro-4-(2-(1- methyl-1H-pyrazol- 4-yl)thieno[3,2- b]pyridin-7-yloxy)phenylcarbamo thioyl)-2- phenylacetamide ¹H NMR(400 MHz, DMSO-d₆)δ ppm: 12.50(s, 1H), 11.85(s, 1H), 8.47(d, J=5.6 Hz, 1H), 8.31(s, 1H),8.02(d, J=12.0 Hz, 1H), 7.99(s, 1H), 7.70(s, 1H), 7.55-7.52(m, 2H),7.38-7.32(m, 4H), 7.31-7.28(m, 1H), 6.60(d, J=5.6 Hz, 1H), 3.89(s, 3H),3.83(s, 2H). 13r 82

N-(3-Fluoro-4-(2-(6- morpholinopyrimidin- 4-yl)thieno[3,2- b]pyridin-7-yloxy)phenylcarbamo thioyl)-2- phenylacetamide ¹H NMR(400 MHz, DMSO-d₆)δ ppm: 12.48(s, 1H), 11 .82(s, 1H), 8.60(s, 1H), 8.56(d, J=5.6 Hz, 1H),8.55(s, 1H), 8.03(d, J=12.0 Hz, 1H), 7.66(s, 1H), 7.58-7.52(m, 2H),7.37-7.31(m, 4H), 7.31-7.24(m, 1H), 6.70(d, J=5.6 Hz, 1H), 3.82(s, 2H),3.78-3.68(m, 8H).

Example 83N-(4-(2-(1H-Imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenylcarbamothioyl)-2-phenylacetamide(113) Step 1. 1-((2-(Trimethylsilyl)ethoxy)methyl)-1H-imidazole (107)

To a stirred suspension of NaH (60% dispersion in oil, 0.65 g, 16.2mmol) at 0° C. was added imidazole (1 g, 14.7 mmol) in THF (14 mL). Themixture was warmed to room temperature over 30 min, then re-cooled to 0°C. followed by an addition of (2-(chloromethoxy)ethyl)trimethylsilane(2.73 ml, 15.4 mmol). The combined mixture was warmed to roomtemperature over 1 h, quenched with saturated aqueous ammonium chloride,concentrated to dryness and partitioned between water and EtOAc. Organicphase was collected, dried over anhydrous sodium sulfate, filtered andevaporated. The residue was purified by column chromatography (eluentsEtOAc, then MeOH/EtOAc 20:80), to afford the title compound (2.04 g, 70%yield) as a white solid. MS (m/z) 199.3 (M+H).

Step 2. 2-Bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (108)

To a solution of 107 (100 mg, 0.50 mmol) in acetonitrile (1 mL) at roomtemperature was added cyanogen bromide (107 mg, 1.0 mmol) and themixture was allowed to stir at room temperature for 3 h, concentrated todryness and partitioned between EtOAc and water. The organic phase wascollected, dried over anhydrous sodium sulfate and concentrated todryness. The residue was purified by column chromatography (eluentsEtOAc/hexane 25:75, then EtOAc), to afford the title compound 108 (45mg, 32% yield) as a colorless oil. MS (m/z) 277.0/279.0 (M+H).

Step 3.7-Chloro-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)thieno[3,2-b]pyridine(109)

Starting from the compound 98 (scheme 19) and following the proceduredescribed above for the synthesis of compound 10 (example 12, scheme 2)but substituting 2-bromothiazole in the step 2 for the bromide 108,title compound 109 was obtained as a white solid (22 mg, 41% yield). MS(m/z) 366.1/368.1 (M+H).

Step 4.7-(2-Fluoro-4-nitrophenoxy)-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)thieno[3,2-b]pyridine(110)

Following the procedure described above for the synthesis of compound 11(example 12, step 3, scheme 2) but substituting compound 10 for compound109, title compound 110 was obtained as a yellow solid (104 mg, 50%yield). MS (m/z) 487.3 (M+H).

Steps 5-6.N-(3-Fluoro-4-(2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(112)

Following the procedure described above for the synthesis of compound13a (example 12, steps 4-5, scheme 2) but substituting compound 11 forcompound 110 and using intermediate amine 111 (instead of amine 12),title compound 112 was obtained as a beige solid (48 mg, 33% yield). MS(m/z) 634.3 (M+H).

Step 7.N-(4-(2-(1H-Imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenylcarbamothioyl)-2-phenylacetamide(113)

A solution of 112 (21 mg, 0.033 mmol) in 4N HCl in dioxane (3.5 mL) wasallowed to stir at 55° C. for 1 h. The mixture was then cooled andsolvent was removed under reduced pressure. The resultant gum wastriturated with ether several times to form a solid material that wasdried under high vacuum to afford the product 113 as a beige solid (5mg, 28% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.50 (1H, s), 11.84(1H, s), 8.66 (1H, d, J=5.67 Hz), 8.39 (1H, s), 8.06 (1H, d, J=12.72Hz), 7.68 (2H, s), 7.59-7.58 (2H, m), 7.36-7.30 (5H, m), 6.86 (1H, d,J=5.48 Hz), 3.83 (2H, s). MS (m/z) 504.1 (M+H).

Example 842-(7-(2-Fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)thieno[3,2-b]pyridin-2-yl)-1-methyl-N-(2-morpholinoethyl)-1H-imidazole-5-carboxamide(117) Step 1. 1-Methyl-N-(2-morpholinoethyl)-1H-imidazole-5-carboxamide(115)

To a suspension of 1-methyl-1H-imidazole-5-carboxylic acid (0.92 g, 7.3mmol) [Rapoport, H.; et al.; Synthesis 1988; 767.] in dichloromethane(10 ml), was added oxalyl chloride (2.6 ml, 29.2 mmol) and the reactionmixture was heated to reflux for 1 h, cooled, concentrated to dryness toform acid chloride 114 (1.05 g, 100%) which was used withoutcharacterization and further purification.

To a suspension of the acid chloride 114 (1.05 g, 7.3 mmol) in THF (10mL) was added 2-morpholinoethanamine (2.38 g, 18.5 mmol). The mixturewas stirred at room temperature for 1 h, concentrated to dryness and theresidue was purified by column chromatography (eluentchloroform/MeOH/ammonium hydroxide, 100:2:0.5), to afford the titlecompound 115 (551 mg, 32% yield) as a white solid. MS (m/z) 239.1 (M+H).

Step 2.2-Bromo-1-methyl-N-(2-morpholinoethyl)-1H-imidazole-5-carboxamide (116)

To a solution of 115 (550 mg, 2.31 mmol) in acetonitrile (5 mL) wasadded cyanogen bromide (489 mg, 4.6 mmol). The reaction flask wascovered with aluminum foil and the mixture was allowed to stir at roomtemperature for 18 h. The solvent was removed under reduced pressure andthe residue was purified by column chromatography (eluents 100% EtOAc to30% MeOH/EtOAc), to afford title compound 116 as a beige solid (230 mg(31%). MS (m/z) 317.1/319.1 (M+H).

Step 3.2-(7-(2-Fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)thieno[3,2-b]pyridin-2-yl)-1-methyl-N-(2-morpholinoethyl)-1H-imidazole-5-carboxamide(117)

Following the procedures described above for the synthesis of compound13a (example 12, scheme 2) but substituting trimethyltin chloride in thestep 1 for tributyltin chloride and 2-bromothiazole in the step 2 forthe bromide 116, title compound 117 was synthesized. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 8.55 (1H, d, J=5.28 Hz), 8.47 (1H, br), 8.04 (1H, s),7.97 (1H, d, J=12.52 Hz), 7.67 (1H, s), 7.49 (2H, br), 7.33-7.32 (4H,m), 7.26 (1H, m), 6.70 (1H, d, J=5.09 Hz), 4.18 (3H, s), 3.84 (2H, s),3.57 (4H, br), 2.47-2.33 (8H, m). MS (m/z) 674.3 (M+H).

Examples 85 and 86 Methyl2-(7-(2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)thieno[3,2-b]pyridin-2-yl)-1-methyl-1H-imidazole-5-carboxylate(123), andN-(3-Fluoro-4-(2-(5-(hydroxymethyl)-1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(124) Step 1. Methyl 2-bromo-1-methyl-1H-imidazole-5-carboxylate (118)

Following the procedure described above for the compound 116 (scheme 21)but replacing compound 115 with methyl1-methyl-1H-imidazole-5-carboxylate, title compound 118 was obtained asa beige solid (373 mg, 49% yield). MS (m/z) 219.1/221.1 (M+H).

Step 2. Methyl2-(7-chlorothieno[3,2-b]pyridin-2-yl)-1-methyl-1H-imidazole-5-carboxylate(119)

Starting from the compound 98 (scheme 19) and following the proceduredescribed above for the synthesis of compound 10 (example 12, scheme 2)but substituting 2-bromothiazole in the step 2 for the bromide 118,title compound 119 was obtained as a white solid (580 mg, 100% yield).MS (m/z) 308.1/310.0 (M+H).

Step 3. Methyl2-(7-(2-fluoro-4-nitrophenoxy)thieno[3,2-b]pyridin-2-yl)-1-methyl-1H-imidazole-5-carboxylate(120)

Following the procedure described above for the synthesis of compound 11(example 12, step 3, scheme 2) but substituting compound 10 for compound119, title compound 120 was obtained as a yellow solid (254 mg, 31%yield). MS (m/z) 429.1 (M+H).

Step 4. Methyl2-(7-(4-amino-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)-1-methyl-1H-imidazole-5-carboxylate(121) and(2-(7-(4-amino-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)-1-methyl-1H-imidazol-5-yl)methanol(122)

Following the procedure described above for the synthesis of compound 12(example 12, step 4, scheme 2) but substituting compound 11 for compound120, title compounds 121 and 122 were obtained as white solids (39 mg,21% yield and 56 mg, 32% yield). MS (m/z) 399.1 (M+H) and MS (m/z) 371.1(M+H) respectively.

Step 5. Methyl2-(7-(2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)thieno[3,2-b]pyridin-2-yl)-1-methyl-1H-imidazole-5-carboxylate(123)

Following the procedure described above for the synthesis of compound13a (example 12, step 3, scheme 2) but substituting compound 12 forcompound 121, title compound 123 was obtained as a beige solid (35 mg,63% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.48 (1H, s), 11.82 (1H,s), 8.58 (1H, dd, 5.48, 0.98 Hz), 8.13 (1H, d, J=0.98 Hz), 8.03 (1H, d,J=12.52 Hz), 7.81 (1H, d, J=1.17 Hz), 7.55-7.54 (2H, m), 7.36-7.31 (4H,m), 7.27 (1H, m), 6.74 (1H, d, J=5.48 Hz), 4.21 (3H, s), 3.83 (3H, s),3.83 (2H, s). MS (m/z) 576.2 (M+H).

Step 5a.N-(3-Fluoro-4-(2-(5-(hydroxymethyl)-1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(124)

Following the procedure described above for the synthesis of compound13a (example 12, step 3, scheme 2) but substituting compound 12 forcompound 122, title compound 124 was obtained as a beige solid (32 mg,39% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.48 (1H, s), 11.82 (1H,s), 8.58 (1H, dd, 5.48, 0.98 Hz), 8.13 (1H, d, J=0.98 Hz), 8.03 (1H, d,J=12.52 Hz), 7.81 (1H, d, J=1.17 Hz), 7.55-7.54 (2H, m), 7.36-7.31 (4H,m), 7.27 (1H, m), 6.74 (1H, d, J=5.48 Hz), 4.21 (3H, s), 3.83 (3H, s),3.83 (2H, s). MS (m/z) 576.2 (M+H).

Example 87N-(4-(2-(N,N-Diethylcarbamimidoyl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenylcarbamothioyl)-2-phenylacetamide(130) Step 1. 7-Chlorothieno[3,2-b]pyridine-2-carbaldehyde oxime (125)

To a solution of aldehyde 14 (scheme 3) in MeOH was added NH₂OH×HCl (227mg, 3.26 mmol) in water (0.5 mL) and the mixture was stirred at roomtemperature for 0.5 h. The solvents were removed by under reducedpressure and the residue was partitioned between EtOAc and water. Theorganic phase was dried over anhydrous sodium sulfate, filtered andevaporated to dryness to afford the title compound 125 (458 mg, 85%yield) as a white solid. MS (m/z) 213.1/215.1 (M+H).

Step 2. 7-Chlorothieno[3,2-b]pyridine-2-carbonitrile (126)

A solution of the oxime 125 (100 mg, 0.47 mmol) in acetic anhydride (2ml) was set to reflux for 3 h and then at 90° C. for 48 h. The aceticanhydride was removed under reduced pressure and the residue waspartitioned between a cold aqueous K₂CO₃ solution and EtOAc. The organicphase was dried over anhydrous sodium sulfate, concentrated to drynessand remained solid was purified by column chromatography, eluents 25%EtOAc/hexane (25:75), then 100% EtOAc, to afford the title compound 126(65 mg, 71% yield). MS (m/z) 195.1/197.1 (M+H).

Step 3. 7-(2-Fluoro-4-nitrophenoxy)thieno[3,2-b]pyridine-2-carbonitrile(127)

Following the procedure described above for the synthesis of compound 11(example 12, step 3, scheme 2) but substituting compound 10 for compound126, title compound 127 was obtained as a yellow solid (114 mg, 60%yield). MS (m/z) 316.0 (M+H).

Step 4.N,N-Diethyl-7-(2-fluoro-4-nitrophenoxy)thieno[3,2-b]pyridine-2-carboximidamide(128)

To a solution of nitrile 127 (116 mg, 0.37 mmol) in MeOH (3 mL) wasadded NaOMe (25% in MeOH, 0.09 ml, 0.39 mmol) and the mixture wasallowed to stir at room temperature for 18 h. Subsequently, Et₂NH×HCl(1.01 g, 9.25 mmol) was added and the mixture was heated to reflux for12 h., cooled to room temperature and the solvent was removed underreduced pressure. The residue was partitioned between EtOAc andsaturated aqueous ammonium chloride, the organic phase was dried overanhydrous sodium sulfate, filtered and concentrated to dryness. Theremained solid was purified by column chromatography (eluents EtOAc thenCHCl₃/MeOH/NH₄OH 44:5:0.5), to afford the title compound 128 (30 mg, 21%yield) as a white solid. MS (m/z) 389.2 (M+H).

Steps 4-5.N-(4-(2-(N,N-Diethylcarbamimidoyl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenylcarbamothioyl)-2-phenylacetamide(130)

Following the procedure described above for the synthesis of compound13a (example 12, steps 4-5, scheme 2) but substituting compound 11 forcompound 128 and using intermediate amine 129 (instead of amine 12),title compound 130 was obtained as a beige solid (5 mg, 13% yield). ¹HNMR (DMSO) δ (ppm): 8.58 (1H, d, J=5.48 Hz), 8.29 (1H, s), 8.02 (1H, d,J=11.35 Hz), 7.81 (1H, d, J=2.54 Hz), 7.53 (2H, br), 7.34-7.33 (5H, m),6.74 (1H, d, J=5.28 Hz), 3.83 (2H, s), 3.40 (4H, q, J=6.91 Hz), 1.16(6H, t, J=6.95 Hz). MS (m/z) 536.2 (M+H).

Example 88N-(3-Fluoro-4-(2-(morpholinomethyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(134) Step 1. 4-((7-Chlorothieno[3,2-b]pyridin-2-yl)methyl)morpholine(131)

To a solution of aldehyde 14 (scheme 3) (316 mg, 1.6 mmol) andmorpholine (0.15 ml, 1.52 mmol) in MeOH (20 mL) was added acetic acid(0.88 ml, 15 mmol), followed by sodium cyanoborohydride (105 mg, 1.67mmol). The resultant mixture was allowed to stir for 18 h, quenched withsaturated aqueous potassium carbonate solution (5 mL), evaporated underreduced pressure and the residue was partitioned between EtOAc andwater. The organic phase was dried over anhydrous sodium sulfate,concentrated to dryness and the remained solid was purified by columnchromatography, eluents EtOAc/hexane (30:70), then MeOH/EtOAc (1:99), toafford the title compound 131 (120 mg, 29% yield). MS (m/z) 269.0/271.0(M+H).

Step 2.4-((7-(2-Fluoro-4-nitrophenoxy)thieno[3,2-b]pyridin-2-yl)methyl)morpholine(132)

Following the procedure described above for the synthesis of compound 11(example 12, step 3, scheme 2) but substituting compound 10 for compound131, title compound 132 was obtained as a yellow solid (110 mg, 69%yield). MS (m/z) 390.1 (M+H).

Steps 3-4.N-(3-Fluoro-4-(2-(morpholinomethyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(134)

Following the procedure described above for the synthesis of compound13a (example 12, steps 4-5, scheme 2) but substituting compound 11 forcompound 132 and using intermediate amine 133 (instead of amine 12),title compound 134 was obtained as a white solid (38 mg, 27% yield). ¹HNMR (DMSO) δ (ppm): 12.89 (1H, s), 12.24 (1H, s), 8.87 (1H, d, J=4.71Hz), 8.42 (1H, d, J=12.13 Hz), 7.95-7.88 (3H, m), 7.76-7.68 (5H, m),7.00 (1H, d, J=5.28 Hz), 4.26-4.25 (4H, m), 4.02 (4H, br), 3.76 (2H, s),2.90 (2H, s). MS (m/z) 537.2 (M+H).

Examples 89-92

-   (S)-tert-Butyl    1-(7-(2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)thieno[3,2-b]pyridine-2-carbonyl)pyrrolidine-2-carboxylate    (135a)-   (R)-tert-Butyl    3-((7-(2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)thieno[3,2-b]pyridine-2-carboxamido)methyl)pyrrolidine-1-carboxylate    (135b)-   (R)—N-(4-(2-(3-(Dimethylamino)pyrrolidine-1-carbonyl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenylcarbamothioyl)-2-phenylacetamide    (135c), and-   N-(3-Fluoro-4-(2-(piperidine-1-carbonyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide    (135d)

Compounds 135a-d (examples 89-92) were obtained following the proceduresdescribed above for the synthesis of compound 8a (example 1, scheme 1).Characterization of 135a-d is provided in Table 11.

TABLE 11 Characterization of compounds 135a-d(examples 89-92)

135 a-d: Examples 89-92 Cpd Ex R Name Characterization 135a 89

(S)-tert-Butyl 1- (7-(2-fluoro-4-(3- phenylacetyl) thioureido)phenoxy)thieno[3,2- b]pyridine-2- carbonyl)pyrro- lidine-2-carboxylate ¹HNMR(400 MHz, DMSO-d₆) δ ppm: 12.48(s, 1H), 11.82(s, 1H), 8.61(d, J=5.6Hz, 0.7H), 8.58(d, J=5.6 Hz, 0.3H), 8.10(s, 0.7H), 8.03(bd, J=12.0 (2Hz,1H), 7.86(s, 0.3H), 7.57-7.51(m, 2H), 7.47-7.20(m, 5H), 6.77(d, J=5.6Hz, 0.7H), 6.75(d, J=5.6 Hz, 0.3H), 5.02-4.97(m, 0.3H), 4.20(dd, J=3.2and 8.4 Hz, 0.7H), 3.97(t, J=6.8 Hz, 1.4H), 3.82(s, 1.4H), 3.80(t, J=6.8Hz, 0.6H), 3.55(s, 0.6H), 2.3-1.10(m, 5H), 1.41(s, 6.3H), 1.19(s, 2.7H).135b 90

(R)-tert-Butyl 3- ((7-(2-fluoro-4- (3-(2- phenylacetyl)thioureido)phenoxy) thieno[3,2- b]pyridine-2- carboxamido)methyl)pyrrolidine-1- carboxylate ¹H NMR(400 MHz, DMSO-d₆) δ ppm:12.48(s, 1H), 11.81(s,1H), 9.05- 8.90(m, 1H), 8.58(d, J=5.6 Hz, 1H),8.32-8.22(m, 1H), 8.02(d, J=11.6 Hz, 1H), 7.56-7.52(m, 2H), 7.36-7.30(m,4H), 7.30-7.24(m, 1H), 6.73(d, J=5.6 Hz, 1H), 4.00-3.90(m, 1H), 3.82(s,2H), 3.54-3.20(m, 4H), 1.91-1.74(m, 4H), 1.39(bs, 9H). 135c 91

(R)-N-(4-(2-(3- (Dimethylamino) pyrrolidine-1- carbonyl)thieno[3,2-b]pyridin-7- yloxy)-3- fluorophenyl carbamothioyl)-2- phenylacetamide¹H NMR(400 MHz CDCl3) δ ppm: 12.54(s, 1H), 8.80(s, 1H), 8.54(d, 1H,J=5.5 Hz), 8.14(s, 1H), 7.96(dd, 1H, J=11.4/2.1 Hz), 7.52-7.26(m, 6H),6.63 (d, 1H, J=5.5 Hz), 4.35-3.52(m, 5H), 3.80(s, 2H), 2.79(s, 6H),2.70-2.40(m, 2H). 135d 92

N-(3-Fluoro-4-(2- (piperidine-1- carbonyl)thieno[3, 2-b]pyridin-7-yloxy)phenyl carbamothioyl)-2- phenylacetamide LRMS(M + 1) 549.3(100%),550.3 (32%).

Example 93N-(3-Fluoro-4-(2-(piperidine-1-carbonyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamidehydrochloride (136a)

N-(3-Fluoro-4-(2-(piperidine-1-carbonyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(135d, example 92) (686 mg, 1.25 mmol) was solubilized in THF (2 mL);dichloromethane (4 mL) and 1M hydrogen chloride in ether (1.5 mL, 1.5mmol) were successfully added. The reaction mixture was stirred for 1hour, the solvents were partially evaporated under reduced pressure toform a precipitate, which was collected by filtration, to afford thetitle compound 136a (380 mg, 65% yield) as a light-yellow solid.Characterization of this material is provided in Table 12.

Example 94N-(3-Fluoro-4-(2-(pyrrolidine-1-carbonyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamidehydrochloride (136b)

Following the procedure described above for the synthesis of compound136a (example 93) but substituting compound 135d (example 92, table 11)for the compound 8o (example 37, table 6), title compound 136b wasobtained. Characterization of this material is provided in Table 12.

Example 95(S)-1-(7-(2-Fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)thieno[3,2-b]pyridine-2-carbonyl)pyrrolidine-2-carboxylicacid hydrochloride (136c)

Following the procedure described above for the synthesis of compound136a (Example 93) but substituting compound 135d (example 92, table 11)for the compound 135a (Example 89, Table 11), title compound 136c wasobtained. Characterization of this material is provided in Table 12.

Example 96N-(4-(2-(Azepane-1-carbonyl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenylcarbamothioyl)-2-phenylacetamidehydrochloride (136d)

Title compound 136d was obtained following the procedures describedabove for the synthesis of compound 136a (example 93, table 12).Characterization of 136d is provided in Table 12.

TABLE 12 Characterization of compounds 136a-d(examples 93-96)

136 a-d: Examples 93-96 Cpd Ex R Name Characterization 136a 93

N-(3-Fluoro-4-(2- (piperidine-1- carbonyl)thieno[3,2- b]pyridin-7-yloxy)phenylcarba- mothioyl)-2- phenylacetamide hydrochloride ¹H NMR(400MHz DMSO-d₆) δ ppm: 12.49(s, 1H), 11.83(s, 1H), 8.65(d, 1H, J=5.7 Hz),8.05(d, 1H, J=11.3 Hz), 7.82(s, 1H), 7.56-7.55 (m, 2H), 7.34-7.26(m,5H), 6.84(d, 1H, J=5.7 Hz), 3.83(s, 2H), 3.61-3.58 (m, 4H), 1.65-1.09(m,6H). 136b 94

N-(3-Fluoro-4-(2- (pyrrolidine-1- carbonyl)thieno[3,2- b]pyridin-7-yloxy)phenylcarba- mothioyl)-2- phenylacetamide hydrochloride ¹H NMR(400MHz, DMSO-d₆) δ ppm: 12.49(s, 1H), 11.82(s, 1H), 8.64(d, J=5.6 Hz, 1H),8.08-8.01(m, 1H), 8.05(s, 1H), 7.58-7.53(m, 1H), 7.36-7.31(m, 4H),7.30-7.24(m, 1H), 6.82(d, J=5.6 Hz, 1H), 3.85(t, J=6.4 Hz, 2H), 3.82(s,2H), 3.54(t, J=6.4 Hz, 2H), 1.97(quin, J=6.4 Hz, 2H), 1.89(quin, J=6.4Hz, 2H). 136c 95

(S)-1-(7-(2-Fluoro-4- 3-(2- phenylacetyl)thiou- reido)phenoxy)thieno[3,b]pyridine-2- carbonyl)pyrrolidine- 2-carboxylic acid hydrochloride ¹HNMR(400 MHz, DMSO-d₆) δ ppm: 12.49(s, 1H), 11.82(s, 1H), 8.67(d, J=5.6Hz, 0.7H), 8.63(d, J= 5.6 Hz, 0.3H), 8.12(s, 0.7H), 8.05(d, J= 21.0 Hz,1H), 7.88(s, 0.3H), 7.58- 7.54(m, 2H), 7.37-7.10(m, 4H), 7.30- 7.24(m,1H), 6.85(d, J=5.6 Hz, 0.7H), 6.8 1(d, J=5.6 Hz, 0.3H), 5.03-4.99(m,0.3H), 4.48(dd, J=4.4 and 8.0 Hz, 0.7H), 3.98(t, J=7.2 Hz, 1.4H),3.82(s, 2H), 3.68-3.60(m, 0.6H), 2.32-2.25(m, 1H), 2.08- 1.90(m, 3H).136d 96

N-(4-(2-(Azepane-1- carbonyl)thieno[3,2- b]pyridin-7-yloxy)-3-fluorophenylcarbamo- thioyl)-2- phenylacetamide hydrochloride ¹H NMR(400MHz DMSO-d₆) δ ppm: 12.49(s, 1H), 11.83(s, 1H), 8.64(d, 1H, J=5.7 Hz),8.04(d, 1H, J=11.5 Hz), 7.85(s, 1H), 7.56-7.55 (m, 2H), 7.34-7.26(m,5H), 6.81(d, 1H, J=5.5 Hz), 3.83(s, 2H), 3.67-3.56 (m, 4H), 1.76-1.57(m,8H).

Example 97(S)-7-(2-Fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)-N-(pyrrolidin-3-ylmethyl)thieno[3,2-b]pyridine-2-carboxamidehydrochloride (137a)

To a solution of 135b (table 11) (16 mg, 0.028 mmol) in CH₂Cl₂ (15 mL)was added TFA (1 mL). The reaction mixture was stirred at roomtemperature until the reaction is complete, then the reaction mixturewas quenched with saturated aqueous sodium bicarbonate solution aextracted with DCM. The extract was concentrated, the residue wasdissolved in DCM (15 mL) and hydrogen chloride (0.5M in ether, 46 μL,0.046 mmol) was added. The reaction mixture was stirred for one hour,the solvents were partially evaporated under reduced pressure to form aprecipitate, which was collected by filtration, to afford the titlecompound 137a (10 mg, 87% yield) as a white solid. ¹H NMR (400 MHz,DMSO-d₆) δ ppm: 12.48(s, 1H), 11.82 (s, 1H), 9.49-9.43 (m, 1H), 9.24(bs,1H), 8.74(bs, 1H), 8.62(d, J=5.6 Hz, 1H), 8.38 (s, 1H), 8.03(d, J=12.0Hz, 1H), 7.58-7.5 (m, 2H), 7.3-7.30 (m, 4H), 7.30-7.24 (m, 1H), 6.79(d,J=5.6 Hz, 1H), 3.80-3.54 (m, 3H), 3.30-3.20 (m, 1H), 3.20-3.10 (m, 1H),2.12-2.02(m, 1H), 2.00-1.95 (m, 2H), 1.74-1.63 (m, 1H).

Example 987-(2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)-N-(2-(methylamino)ethyl)thieno[3,2-b]pyridine-2-carboxamidehydrochloride (137b) Steps 1-7. tert-Butyl2-(7-(2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)thieno[3,2-b]pyridine-2-carboxamido)ethyl(methyl)carbamate(138)

Following the procedures described above for the synthesis of compound8a (Example 1, scheme 1) but replacing dimethyl amine with tert-butyl2-aminoethyl(methyl)carbamate, title compound 138 was obtained (13%).LRMS (M+1) 638.2 (100%).

Step 8.7-(2-Fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)-N-(2-(methylamino)ethyl)thieno[3,2-b]pyridine-2-carboxamidehydrochloride (137b)

Following the procedure described above for the synthesis of 137a butreplacing compound 135b with compound 138, title compound 137b wasobtained as an HCl salt in 65% yield. ¹H NMR (400 MHz, DMSO-d₆) δ ppm:12.49 (s, 1H), 11.83 (s, 1H), 9.39(t, J=5.2 Hz, 1H), 8.80(bs, 1H),8.62(d, J=5.6 Hz, 1H), 8.39 (s, 1H), 8.04(d, J=11.6 Hz, 1H), 7.97(bs,1H), 7.58-7.50 (m, 2H), 7.37-7.31 (m, 4H), 7.31-7.24 (m, 1H), 6.80(d,J=5.6 Hz, 1H), 3.78-3.71(m, 0.5H), 3.61(q, J=6.0 Hz, 1H), 3.21-3.24 (m,0.5H), 3.18-3.04 (m, 2H), 2.60(t, J=4.8 Hz, 2H).

Examples 99 and 100

-   N-(3,5-Dichloro-4-(2-(pyrrolidine-1-carbonyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide (142)    and-   7-(2,6-dichloro-4-(3-(2-phenylacetyl)thioureido)phenoxy)-2-(pyrrolidine-1-carbonyl)thieno[3,2-b]pyridin-4-ium    chloride (143)

Steps 1-4. (7-Chlorothieno[3,2-b]pyridin-2-yl)(pyrrolidin-1-yl)methanone(139)

Following the procedures described above for the synthesis of compound 5(scheme 1, example 1) but replacing dimethyl amine in the step 4 forpyrrolidine, title compound 139 was obtained. LRMS (M+1) 267.1 (100%).

Step 5.(7-(2,6-Dichloro-4-nitrophenoxy)thieno[3,2-b]pyridin-2-yl)(pyrrolidin-1-yl)methanone(140)

Starting from the compound 139 and following the procedure describedabove for the synthesis of compound 6 (scheme 1, example 1) butreplacing 2-fluoro-4-nitrophenol with 2,6-dichloro-4-nitrophenol, titlecompound 140 was obtained in 69% yield. LRMS (M+1) 438.0 (100%), 439.1(20%), 440.1 (70%).

Steps 6-7.N-(3,5-Dichloro-4-(2-(pyrrolidine-1-carbonyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(142)

Starting from the nitro compound 140 and following the proceduresdescribed above for the synthesis of 8a (steps 6-7, scheme 1, example 1)title compound 142 was obtained in 49% yield. LRMS (M+1) 585.3 (100%),586.2 (34%), 587.3 (72%).

7-(2,6-Dichloro-4-(3-(2-phenylacetyl)thioureido)phenoxy)-2-(pyrrolidine-1-carbonyl)thieno[3,2-b]pyridin-4-iumchloride (143)

Following the procedure described above for the synthesis of compound136a (Table 12, Example 93) but replacing compound 135d with compound142, title compound 143 was obtained in 42% yield. Characterization of143 is provided in the Table 13.

Examples 101 and 102N-(3-Chloro-4-(2-(pyrrolidine-1-carbonyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamidehydrochloride (144) andN-(3-Methyl-4-(2-(pyrrolidine-1-carbonyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamidehydrochloride (145)

Compounds 144-145 (examples 101-102) were obtained following theprocedures described above for the synthesis of compound 143 (example100). Characterization of compounds 144-145 is provided in the Table 13.

Examples 103 and 1042-Phenyl-N-(4-(2-(pyrrolidine-1-carbonyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)acetamide(146) andN-(3-(Dimethylamino)-4-(2-(pyrrolidine-1-carbonyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(147)

Compounds 146-147 (Examples 103-104) were obtained following theprocedures described above for the synthesis of compound 142 (Example99). Characterization of compounds 145-147 is provided in the Table 13.

TABLE 13 Characterization of compounds 143-146(examples 99-103)

143-147: Examples 100-104 Cpd Ex Ar Name Characterization 143 100

N-(3,5-Dichloro-4-(2- (pyrrolidine-1- carbonyl)thieno[3,2- b]pyridin-7-yloxy)phenylcarbamo- thioyl)-2-phenylacetamide hydrochloride ¹H NMR(400MHz, DMSO-d₆) δ ppm: 12.44(s, 1H), 11.91(s, 1H), 8.61(d, 1H, J=5.5 Hz),8.10 (s, 2H), 8.06(s, 1H), 7.34-7.27 (m, 5H), 6.68(d, 1H, J=5.5 Hz),3.88-3.83(m, 4H), 3.70-3.40(m, 2H), 1.99-1.18(m, 4H). 144 101

N-(3-Chloro-4-(2- (pyrrolidine-1- carbonyl)thieno[3,2- b]pyridin-7-yloxy)phenylcarbamo- thioyl)-2-phenylacetamide hydrochloride ¹H NMR(400MHz, DMSO-d₆) δ ppm: 12.43(s, 1H), 11.83(s, 1H), 8.65(d, 1H, J=5.7 Hz),8.14 (d, 1H, J=2.3 Hz), 8.06(s, 1H), 7.70(dd, 1H, J=8.8/2.5 Hz), 7.55(d, 1H, J=8.8 Hz), 7.34-7.26(m, 5H), 6.74(d, 1H, J=5.7 Hz), 3.87-3.83(m, 4H), 3.56-3.53(m, 2H), 1.99- 1.88(m, 4H). 145 102

N-(3-Methyl-4-(2- (pyrrolidine-1- carbonyl)thieno[3,2- b]pyridin-7-yloxy)phenylcarbamo- thioyl)-2-phenylacetamide hydrochloride ¹H NMR(400MHz, DMSO-d₆) 6 ppm: 12.43(s, 1H), 11.74(s, 1H), 8.62(d, 1H, J=5.7 Hz),8.04 (s, 1H), 7.69-7.65(m, 2H), 7.43- 7.26(m, 6H), 6.67(d, 1H, J=5.7Hz), 3.87-3.82(m, 4H), 3.67-3.38 (m, 2H), 2.13(s, 3H), 1.99-1.18 (m,4H). 146 103

2-Phenyl-N-(4-(2- (pyrrolidine-1- carbonyl)thieno[3,2- b]pyridin-7-yloxy)phenylcarbamo- thioyl)acetamide ¹H NMR(400 MHz, DMSO-d₆) δ ppm:12.41(s, 1H), 11.75(s, 1H), 8.68(d, J=5.6 Hz, 1H), 8.06(s, 1H), 7.77(d,J=8.8 Hz, 2H), 7.36(d, J=8.8 Hz, 2H), 7.34-7.31(m, 4H), 7.30-7.24(m,1H), 6.85(d, J=5.6 Hz, 1H), 3.84(t, J=6.4 Hz, 2H), 3.82(s, 2H), 3.54(t,J=6.4 Hz, 2H), 1.97(quin, J=6.4 Hz, 2H), 1.89(quin, J=6.4 Hz, 2H). 147104

N-(3-(Dimethylamino)- 4-(2-(pyrrolidine-1- carbonyl)thieno[3,2-b]pyridin-7- yloxy)phenylcarbamo- thioyl)-2-phenylacetamide ¹H NMR(400MHz, CDCl₃) δ ppm: 8.48(d, 1H, J=6.1 Hz), 8.27(s, 1H), 7.56(m, 8H), 6.67(m, 1H), 3.91(t, 2H, J=6.8 Hz), 3.78(s, 2H), 3.74(t, 2H, J=6.8 Hz),2.73(s, 6H), 2.19-2.01(m, 4H).

Example 105N-(3-Fluoro-4-(6-(thiazol-2-yl)thieno[3,2-d]pyrimidin-4-yloxy)phenylcarbamothioyl)-2-phenylacetamide(152a) Step 1. 4-Chloro-6-(tributylstannyl)thieno[3,2-d]pyrimidine (148)

Starting from 4-chloro-thieno[3,2-d]pyrimidine (20, scheme 4) andfollowing the procedure described above for the synthesis of tributyltincompound 98 (scheme 19), title compound 148 was obtained in 79% yield.LRMS (M+1) 461.1 (100%).

Step 2. 4-Chloro-6-(thiazol-2-yl)thieno[3,2-d]pyrimidine (149)

Starting from the tributyltin compound 148 and following the proceduredescribed above for the synthesis of compound 10 (scheme 2, example 12),title compound 149 was obtained in 81% yield. LRMS (M+1) 254.0 (100%).

Step 3.4-(2-Fluoro-4-nitrophenoxy)-6-(thiazol-2-yl)thieno[3,2-d]pyrimidine(150)

Starting from the bis-aryl compound 149 and following the proceduredescribed above for the synthesis of compound 11 (scheme 2, example 12)title compound 150 was obtained in 65% yield. LRMS (M+1) 375.0 (100%).

Steps 4-5.N-(3-Fluoro-4-(6-(thiazol-2-yl)thieno[3,2-d]pyrimidin-4-yloxy)phenylcarbamothioyl)-2-phenylacetamide(152a)

Starting from the nitro compound 150, following the procedure describedabove for the synthesis of compound 13a (via the intermediate amine 12,scheme 2, example 12), title compound 152a was obtained [viaintermediate3-fluoro-4-(6-(thiazol-2-yl)thieno[3,2-d]pyrimidin-4-yloxy)benzenamine(151)] in 7% yield. Characterization of 152a is provided in the Table14.

Examples 106-108

-   N-(3-Fluoro-4-(6-(pyridin-2-yl)thieno[3,2-d]pyrimidin-4-yloxy)phenylcarbamothioyl)-2-phenylacetamide    (152b)-   N-(3-Fluoro-4-(6-(thiophen-2-yl)thieno[3,2-d]pyrimidin-4-yloxy)phenylcarbamothioyl)-2-phenylacetamide    (152c), and-   N-(3-Fluoro-4-(6-(thiophen-2-yl)thieno[3,2-d]pyrimidin-4-yloxy)phenylcarbamothioyl)-2-phenylacetamide    (152d)

Compounds 152b-d (Examples 106-108) were synthesized according to theScheme 27, similarly to the compound 152a (Example 105).Characterization of 152b-d is provided in the Table 14.

TABLE 14 Characterization of Compounds 152a-d(Examples 105-108) Cpd Ex RName Characterization 152a 105

N-(3-Fluoro-4-(6- (thiazol-2- yl)thieno[3,2- d]pyrimidin-4-yloxy)phenylcarbamo- thioyl)-2- phenylacetamide ¹H NMR(400 MHz, DMSO-d₆)δ ppm: 8.75(s, 1H), 8.32(s, 1H), 8.05(d, J=3.2 Hz, 1H), 8.03(d, J= 3.2Hz, 1H), 7.96-7.88(m, 1H), 7.58-7.50(m, 1H), 7.50-7.43(m, 1H),7.36-7.30(m, 4H), 7.30- 7.23(m, 1H), 3.83(s, 2H). 152b 106

N-(3-Fluoro-4-(6- (pyridin-2- yl)thieno[3,2- d]pyrimidin-4-yloxy)phenylcarbamo- thioyl)-2- phenylacetamide ¹H NMR(400 MHz, DMSO-d₆)δ ppm: 12.44(s, 1H), 11.80(s, 1H), 8.73(s, 1H), 8.70-8.64(m, 1H),8.47(s, 1H), 8.3 8(m, J=8.0 Hz, 1H), 8.00(td, J=2.0 and 8.0 Hz, 1H),7.92(dd, J=2.0 and 12.0 Hz, 1H), 7.55(t, J=8.8 Hz, 1H), 7.53- 7.46(m,2H), 7.36-7.31(m, 4H), 7.30-7.24(m, 1H), 3.82(s, 2H). 152c 107

N-(3-Fluoro-4-(6- (thiophen-2- yl)thieno[3,2- d]pyrimidin-4-yloxy)phenylcarbamo- thioyl)-2- phenylacetamide ¹H NMR(400 MHz, DMSO-d₆)δ ppm: 12.42(s, 1H), 11.80(s, 1H), 8.69(s, 1H), 7.92(dd, J=2.4 and 10.4Hz, 1H), 7.91(s, 1H), 7.82(dd, J=1.2 and 4.8 Hz, 1H), 7.79(dd, J= 1.2and 3.6 Hz, 1H), 7.54(t, J= 8.8 Hz, 1H), 7.47(dd, J=2.4 and 8.8 Hz, 1H),7.36-7.30(m, 4H), 7.30-7.25(m, 1H), 7.24(dd, J=3.6 and 4.8 Hz, 1H),3.82(s, 2H). 152d 108

N-(3-Fluoro-4-(6- (pyrimidin-2- yl)thieno[3,2- d]pyrimidin-4-yloxy)phenylcarbamo- thioyl)-2- phenylacetamide ¹H NMR(400 MHz, DMSO-d₆)δ ppm: 12.44(s, 1H), 11.80(s, 1H), 9.00(s, 1H), 8.98(s, 1H), 8.77(s,1H), 8.37(s, 1H), 7.94(dd, J=2.4 and 12.0 Hz), 7.61(t, J=5.2 Hz, 1H),7.57(t, J=8.8 Hz, 1H), 7.49(dd, J=2.4 and 8.8 Hz, 1H), 7.38-7.31(m, 4H),7.30-7.25(m 1H), 3.83(s, 2H).

Example 109N-(3-Fluoro-4-(2-(4-hydroxyphenyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(155a) Step 1.4-(7-(2-Fluoro-4-nitrophenoxy)thieno[3,2-b]pyridin-2-yl)phenol (153)

To a solution of2-bromo-7-(2-fluoro-4-nitrophenoxy)thieno[3,2-b]pyridine (42, scheme 8)(650 mg, 1.76 mmol) in ethylene glycol dimethyl ether (18 mL) were added4-hydroxyphenylboronic acid (486 mg, 3.52 mmol),tetrakis-triphenylphosphine palladium(0) (203 mg, 0.18 mmol), cesiumfluoride (802 mg, 5.28 mmol) and a solution of sodium bicarbonate (444mg, 5.28 mmol) in water (1 mL). The reaction mixture was purged withnitrogen, heated at 80° C. for 4 hours, quenched with saturated aqueousammonium chloride and extracted with EtOAc. The extract was washed withwater and brine, dried over anhydrous magnesium sulfate, filtered andevaporated under reduced pressure. The residue was purified bytrituration with methanol and ether to afford title compound 153 (418mg, 62% yield) as a yellow solid. LRMS (M+1) 383.1 (100%).

Step 2. 4-(7-(4-Amino-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)phenol(154)

Following the procedure described above for the synthesis of the amine49 (scheme 10, example 55) but substituting nitro compound 48 for thenitro compound 153, title compound 154 was obtained in 99% yield (crudematerial, used in the next step without additional purification). LRMS(M+1) 353.1 (100%).

Step 3.N-(3-Fluoro-4-(2-(4-hydroxyphenyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(155a)

Following the procedure described above for the synthesis of Compound 50(Scheme 10, Example 55) but substituting amine 49 for the amine 154,title Compound 155a was obtained in 3% yield. Characterization of 155ais provided in the Table 14a.

Examples 110-118N-(3-Fluoro-4-(2-(4-methoxyphenyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(155b)N-(3-Fluoro-4-(2-(3-methoxyphenyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(155c)N-(3-Fluoro-4-(2-(3-fluoro-4-methoxyphenyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(155d)N-(3-Fluoro-4-(2-(4-morpholinophenyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(155e)N-(3-Fluoro-4-(2-phenylthieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(155f)N-(3-Fluoro-4-(2-(2-morpholinopyrimidin-5-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(155g)N-(3-Fluoro-4-(2-(2-(2-morpholinoethoxy)pyrimidin-5-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(155h)N-(3-Fluoro-4-(2-(2-methoxyphenyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(155i), andN-(3-Fluoro-4-(2-(4-hydroxy-3-methoxyphenyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(155j)

Compounds 155b-j (Examples 110-118) were prepared similarly to theCompound 155a (Example 109, Scheme 28). Characterization of 155b-j isprovided in the Table 14a.

TABLE 14a

155a–j: Examples 109–118 Characterization of compounds 152a–j (examples109–118) Cpd Ex R Name Characterization 155a 109

N-(3-Fluoro-4-(2-(4- hydroxyphenyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)- 2-phenylacetamide ¹H NMR (400MHz, DMSO-d₆) δ ppm: 12.46(s, 1H), 11.82(s, 1H), 9.95(s, 1H), 8.46(d,1H, J=5.3 Hz), 7.99(d, 1H, J=13.1 Hz), 7.83(s, 1H), 7.70(d, 2H, J=13.1Hz), 7.52–7.51(m, 2H), 7.34–7.27(m, 5H), 6.86(d, 2H, J=8.6 Hz), 6.59(d,1H, J=5.5 Hz), 3.83(s, 2H). 155b 110

N-(3-Fluoro-4-(2-(4- methoxyphenyl)thieno[3,2-b] pyridin-7-yloxy)phenyl-carbamothioyl)-2- phenylacetamide ¹H NMR (400 MHz, DMSO-d₆) δ ppm:12.46(s, 1H), 11.82(s, 1H), 8.48(d, J=5.6 Hz, 1H), 8.00(d, J=7.6 Hz,1H), 7.91(s, 1H), 7.81(d, J=8.8 Hz, 2H), 7.66–7.60(m, 2H), 7.37–7.31(m,4H), 7.31–7.24(m, 1H), 7.05(d, J=8.8 Hz, 2H), 6.61(d, J=5.6 Hz, 1H),3.82(s, 3H). 155c 111

N-(3-Fluoro-4-(2-(3- methoxyphenyl)thieno[3,2-b] pyridin-7-yloxy)phenyl-carbamothioyl)-2- phenylacetamide ¹H NMR (400 MHz, DMSO-d₆) δ ppm:12.46(s, 1H), 11.82(s, 1H), 8.52(d, J=5.6 Hz, 1H), 8.10(s, 1H), 8.01(d,J=12.4 Hz, 1H), 7.56–7.51(m, 2H), 7.46–7.37(m, 3H), 7.37–7.31(m, 4H),7.31–7.24(m, 1H), 7.05–7.00(m, 1H), 6.65(d, J=5.6 Hz, 1H), 3.85(s, 3H),3.82(s, 2H). 155d 112

N-(3-Fluoro-4-(2-(3-fluoro-4- methoxyphenyl)thieno[3,2-b]pyridin-7-yloxy)phenyl- carbamothioyl)-2- phenylacetamide ¹H NMR (400MHz, DMSO-d₆) δ ppm: 12.46(s, 1H), 11.82(s, H), 8.49(d, J=5.6 Hz, 1H),8.01(s, 1H), 8.2–7.76(m, 1H), 7.84(dd, J=2.4 and 12.0 Hz, 1H),7.66–7.61(m, 1H), 7.55–7.51(m, 2H), 7.38–7.10(m, 6H), 6.63(d, J=5.6 Hz,1H), 3.90(s, 3H), 3.82(s, 2H). 155e 113

N-(3-Fluoro-4-(2-(4- morpholinophenyl)thieno[3,2-b]pyridin-7-yloxy)phenyl- carbamothioyl)-2- phenylacetamide ¹H NMR (400MHz, DMSO-d₆) δ ppm: 12.49(s, 1H), 11.85(s, 1H), 8.63(d, J=5.6 Hz, 1H),8.03(d, J=11.6 Hz, 1H), 7.89(s, 1H), 7.79(d, J=8.8 Hz, 2H), 7.63–7.56(m,2H), 7.36–7.31(m, 4H), 7.31–7.25(m, 1H), 7.05(d, J=8.8 Hz, 2H), 6.87(d,J=5.6 Hz, 1H), 3.83(s, 2H), 3.78–3.73(m, 4H), 3.30–3.24(m, 4H). 155f 114

N-(3-Fluoro-4-(2- phenylthieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)- 2-phenylacetamide ¹H NMR (400 MHz, DMSO-d₆)δ ppm: 12.46(s, H), 11.82(s, 1H), 8.52(d, J=5.6 Hz, 1H), 8.06(s, 1H),8.01(d, J=12.4 hz, 1H), 7.88(d, J=6.8 Hz, 2H), 7.58–7.41(m, 5H),7.38–7.31(m, 4H), 7.31–7.24(m, 1H), 6.65(d, J=5.6 Hz, 1H), 3.82(s, 2H).155g 115

N-(3-Fluoro-4-(2-(2- morpholinopyrimidin-5-yl)thieno[3,2-b]pyridin-7-yloxy) phenylcarbamothioyl)-2- phenylacetamide ¹HNMR (400 MHz, DMSO-d₆) δ ppm: 12.46(s, 1H), 11.82(s, 1H), 8.89(s, 2H),8.49(d, J=5.6 hz, 1H), 8.00(d, J=12.0 Hz, 1H), 7.98(s, 1H), 7.56–7.51(m,2H), 7.37–7.31(m, 4H), 7.31–7.24(m, 1H), 6.61(d, J=5.6 Hz, 1H), 3.82(s,2H), 3.82– 3.76(m, 4H), 3.70–3.66(m, 4H). 155h 116

N-(3-Fluoro-4-(2-(2-(2- morpholinoethoxy)pyrimidin-5-yl)thieno[3,2-b]pyridin-7- yloxy)phenylcarbamothioyl)-2-phenylacetamide ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 12.49(s, 1H),11.85(s, 1H), 9.13(s, 2H), 8.56(d, J=5.6 Hz, 1H), 8.18(s, 1H), 8.03(d,J=1.8 Hz, 1H), 7.60–7.54(m, 2H), 7.39–7.32(m, 4H), 7.32–7.25(m, 1H),6.68(d, J=5.6 Hz, 1H), 4.50(t, J=5.6 Hz, 2H), 3.83(s, 2H), 3.57(t, J=4.4Hz, 4H), 2.73(t, J=5.6 Hz, 2H), 2.51–2.44(m, 4H). 155i 117

N-(3-Fluoro-4-(2-(2-methoxy- phenyl)thieno[3,2-b]pyridin-7-yloxy)phenyl- carbamothioyl)-2- phenylacetamide ¹H NMR (400 MHz,DMSO-d₆) δ ppm: 12.51(s, 1H), 11.84(s, 1H), 8.67(d, 1H, J=6.1 Hz), 8.13(s, 1H), 8.08(d, 1H, J= 13.1 Hz), 8.02(dd, 1H, J=7.7/1.5 Hz),7.61–7.60(m, 2H), 7.50(td, 1H, J=7.8/1.7 Hz), 7.35–7.32(m, 4H),7.29–7.26(m, 2H), 7.13(td, 1H, J=7.6/1.1 Hz), 6.88(d, 1H, J=6.1 Hz),4.00 (s, 3H), 3.83(s, 2H). 155j 118

N-(3-Fluoro-4-(2-(4-hydroxy- 3-methoxyphenyl)thieno[3,2-b]pyridin-7-yloxy)phenyl- carbamothioyl)-2- phenylacetamide ¹H NMR (400MHz, DMSO-d₆) δ ppm: 12.49(s, 1H), 11.85(s, 1H), 9.57(s, 1H), 8.49(d,1H, J=5.5 Hz), 8.01(d, 1H, J=13.5 Hz), 7.94(s, 1H), 7.54–7.53(m, 2H),7.44(d, 1H, J=2.3 Hz), 7.38–7.27(m, 6H), 6.88(d, 1H, J=8.2 Hz), 6.61(d,1H, J=4.9 Hz), 3.89(s, 3H), 3.83(s, 2H).

Example 119N-(3-Fluoro-4-(2-(2-hydroxyphenyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(155k)

To a cold (−40° C.) solution of the compound 155i (80 mg, 0.15 mmol) inDCM (3 mL) was added tribromoborane (1M in DCM, 0.60 mL, 0.60 mmol). Thereaction mixture was stirred overnight at room temperature. Water andmethanol were added and the mixture was stirred for additional 20minutes. Organic phase was separated and the aqueous layer was extractedwith EtOAc. Both organic phases were combined, washed with water andbrine, dried over anhydrous magnesium sulfate, filtered and evaporatedunder reduced pressure. The residue was purified by flash chromatography(eluent MeOH-DCM, 2:98) then triturated with methanol, to afford thetitle compound 155k (6 mg, 7% yield), as a light yellow solid. ¹H NMR(400 MHz, DMSO-d₆) δ ppm: 12.47 (d, 1H, J=0.4 Hz), 11.82 (s, 1H), 10.65(s, 1H), 8.48 (d, 1H, J=5.5 Hz), 8.07 (s, 1H), 8.01 (d, 1H, J=11.5 Hz),7.84 (d, 1H, J=7.8 Hz), 7.53-7.49 (m, 2H), 7.38-7.23 (m, 6H), 7.01 (d,1H, J=8.2 Hz), 6.93 (t, 1H, J=7.4 Hz), 6.58 (d, 1H, J=5.5 Hz), 3.83 (s,2H). LRMS (M+1) 530.2 (100%).

Example 120N-(3-Fluoro-4-(2-(3-hydroxyphenyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(155l)

Following the procedure described above for the synthesis of compound155k (example 119, scheme 29) but substituting methoxy-compound 155i forthe methoxy-compound 155c, title compound 155l was prepared in 62%yield. ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 12.49 (s, 1H), 11.84 (s, 1H),8.68(d, J=5.6 Hz, 1H), 8.07(d, J=12.0 Hz, 1H), 7.99 (s, 1H), 7.64-7.56(m, 2H), 7.38-7.24 (m, 8H), 6.96-6.88 (m, 2H), 3.83 (s, 2H).

Example 121N-(3-Fluoro-4-(2-(4-(piperazin-1-yl)phenyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamidedi-hydrochloride (159) Step 1. tert-Butyl4-(4-(7-(2-fluoro-4-nitrophenoxy)thieno[3,2-b]pyridin-2-yl)phenyl)piperazine-1-carboxylate(156)

Starting from the nitro-bromo compound 42, following the proceduredescribed above for the synthesis of compound 48 (scheme 10, example 55)but substituting4,4,5,5-tetramethyl-2-(4-(methylsulfonyl)phenyl)-1,3,2-dioxaborolane for4-(4-(tert-butoxycarbonyl)piperazin-1-yl)phenylboronic acid, titlecompound 156 was obtained in 70% yield. LRMS (M+1) 550.6 (100%).

Step 2. tert-Butyl4-(4-(7-(4-amino-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)phenyl)piperazine-1-carboxylate(157)

Following the procedure described above for the synthesis of amine 49(scheme 10, example 55) but substituting nitro compound 48 for the nitrocompound 156, title compound 157 was obtained in 99% yield (crudematerial, used in the next step without additional purification). LRMS(M+1) 520.2 (100%).

Step 3. tert-Butyl4-(4-(7-(2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)thieno[3,2-b]pyridine-2-yl)phenyl)piperazine-1-carboxylate(158)

Following the procedure described above for the synthesis of compound 50(scheme 10, example 55) but substituting amine 49 for the amine 157,title compound 158 was obtained in 41% yield. LRMS (M+1) 697.2 (100%).

Step 4.N-(3-Fluoro-4-(2-(4-(piperazin-1-yl)phenyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamidedi-hydrochloride (159)

Following the procedure described above for the synthesis of compound137a (scheme 25, example 97) but substituting compound 135b for thecompound 158, title compound 159 was obtained in 21% yield. ¹H NMR (400MHz, DMSO-d₆) δ ppm: 12.48(s, 1H), 11.84 (s, 1H), 9.26(bs, 1H), 8.62(d,J=5.6 Hz, 1H), 8.05(d, J=12.0 Hz, 1H), 7.94 (s, 1H), 7.81(d, J=8.8 Hz,2H), 7.62-7.55 (m, 2H), 7.37-7.31 (m, 4H), 7.31-7.24 (m, 1H), 7.10(d,J=8.8 Hz, 2H), 6.85(d, J=5.6 Hz, 1H), 3.83 (s, 2H), 3.58-3.51 (m, 4H),3.26-3.18 (m, 4H). LRMS (M+1) 597.2 (100%).

Example 122N-(3-Fluoro-4-(2-(3-(2-morpholinoethoxy)phenyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(163a) Step 1.3-(7-(2-Fluoro-4-nitrophenoxy)thieno[3,2-b]pyridin-2-yl)phenol (160)

Starting from the nitrobromo compound 42, following the proceduredescribed above for the synthesis of compound 153 (scheme 28, example109) but substituting 4-hydroxyphenylboronic acid for3-hydroxyphenylboronic acid, title compound 160 was obtained in 66%yield as a gray solid. LRMS (M+1) 383.1 (100%).

Step 2.4-(2-(3-(7-(2-Fluoro-4-nitrophenoxy)thieno[3,2-b]pyridin-2-yl)phenoxy)ethyl)morpholine(161)

Diethylazodicarboxylate (0.6 mL, 3.84 mmol) was added to the solution of160 (1.05 g, 2.75 mmol), 2-morpholinoethanol (0.5 mL, 3.84 mmol) andtriphenylphosphine (1.01 g, 3.84 mmol) in tetrahydrofuran (27 mL). Thereaction mixture was stirred until its completion, quenched withsaturated aqueous ammonium chloride and extracted with EtOAc. Theorganic phase was washed with water and brine, dried over anhydrousmagnesium sulfate, filtered and evaporated under reduced pressure. Theresidue was purified by flash chromatography, eluent MeOH-DCM (2:98) toafford title compound 161 (906 mg, 66% yield) as a light-yellow solid.LRMS (M+1) 496.3 (100%).

Step 3.3-Fluoro-4-(2-(3-(2-morpholinoethoxy)phenyl)thieno[3,2-b]pyridin-7-yloxy)benzenamine(162)

Following the procedure described above for the synthesis of amine 49(scheme 10, example 55) but substituting nitro compound 48 for the nitrocompound 161, title compound 162 was obtained in 91% yield (crudematerial, used in the next step without additional purification). LRMS(M+1) 466.2 (100%).

Step 4.N-(3-Fluoro-4-(2-(3-(2-morpholinoethoxy)phenyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(163a)

Following the procedure described above for the synthesis of compound 50(scheme 10, example 55) but substituting amine 49 for the amine 162,title compound 163a was obtained in 29% yield. Characterization of 163ais provided in the table 15. [LRMS (M+1) 643.3 (100%).

Examples 123-127N-(3-Fluoro-4-(2-(4-(2-morpholinoethoxy)phenyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(163b)N-(3-Fluoro-4-(2-(4-(2-(piperidin-1-yl)ethoxy)phenyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(163c)N-(3-Fluoro-4-(2-(4-(2-(pyridin-2-yl)ethoxy)phenyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamidehydrochloride (163d)N-(3-Fluoro-4-(2-(4-(3-morpholinopropoxy)phenyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(163e) tert-Butyl2-(4-(7-(2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)thieno[3,2-b]pyridin-2-yl)phenoxy)ethyl(methyl)carbamate(163f)

Starting from the phenol 153 (scheme 28, example 109) and following theprocedures described above for the synthesis of 163a (Scheme 31, Example122) title compounds 163b-f were obtained. Characterization of 163b-f isprovided in the Table 15.

Examples 128-129N-(3-Fluoro-4-(2-(3-methoxy-4-(2-morpholinoethoxy)phenyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(163g)N-(3-Fluoro-4-(2-(2-(2-morpholinoethoxy)phenyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamidehydrochloride (163h)

Following the procedures described above for the synthesis of 163a(Scheme 31, example 122) but replacing in the first step3-hydroxyphenylboronic acid with 4-hydroxy-3-methoxyphenylboronic acidor 2-hydroxyphenylboronic acid, title compounds 163g-h were obtained.Characterization of 163g-h is provided in the table 15.

TABLE 15

163a–h: Example 122–128 Characterization of compounds 163a–h (examples122–128) Cpd Ex R Name Characterization 163a 122

N-(3-Fluoro-4-(2-(3-(2- morpholinoethoxy)phenyl)thieno[3,2-b]pyridin-7-yloxy) phenyl-carbamothioyl)-2- phenylacetamide¹H NMR (400 MHz, DMSO-d₆) δ ppm: 12.47 (s, 1H), 11.82 (s, 1H), 8.52 (d,1H, J=5.5 Hz), 8.12 (s, 1H), 8.01 (d, 1H, J=12.1 Hz), 7.54–7.52(m, 2H),7.45–7.26 (m, 8H), 7.04–7.01 (m, 1H), 6.65 (d, 1H, J=5.3 Hz), 4.20 (t,2H, J=5.8 Hz), 3.83 (s, 2H), 3.57 (t, 4H, J=4.6 Hz), 2.73 (t, 2H, J=5.6Hz), 2.51–2.49 (m, 4H). 163b 123

N-(3-Fluoro-4-(2-(4-(2- morpholinoethoxy)phenyl)thieno[3,2-b]pyridin-7-yloxy) phenyl-carbamothioyl)-2- phenylacetamide¹H NMR (400 MHz, DMSO-d₆) δ ppm: 12.46(s, 1H), 11.82(s, 1H), 8.49(s,J=5.6 Hz, 1H), 8.00(d, J=12.0 Hz, 1H), 7.94(s, 1H), 7.90–7.78(m, 2H),7.56–7.38(m, 2H), 7.39–7.22(m, 5H), 7.16–7.02(m, 2H), 6.62(d, J=5.6 H,1H), 4.34–3.90(m, 3H), 3.82(s, 2H), 3.76–2.40(m, 9H). 163c 124

N-(3-Fluoro-4-(2-(4-(2- (piperidin-1-yl)ethoxy)phenyl)thieno[3,2-b]pyridin-yloxy) phenylcarbamothioyl)-2- phenylacetamide ¹HNMR (400 MHz, DMSO-d₆) δ ppm: 8.52(bs, 1H), 8.38(d, J=5.6 Hz, 1H),8.0(dd, J=2.0 and 12.0 Hz, 1H), 7.75(d, J=8.4 Hz, 2H), 7.64(s, 1H),7.44–7.40(m, 1H), 7.38–7.29(m, 5H), 7.29–7.24(m, 1H), 7.07(d, J=8.4 Hz,2H), 6.60(d, J=5.6 Hz, 1H), 4.39–4.31(m, 2H), 3.75(s, 2H), 3.39–3.33(m,2H), 3.20–3.05(m, 4H), 1.89–1.79(m, 4H), 1.70–1.60(m, 2H). 163d 125

N-(3-Fluoro-4-(2-(4-(2- (pyridin-2-yl)ethoxy)phenyl)thieno[3,2-b]pyridin-7-yloxy) phenylcarbamothioyl)-2- phenylacetamidehydrochloride ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 12.48(s, 1H), 11.84(s,1H), 8.81(d, J=4.8 Hz, 1H), 8.61(d, J=5.6 Hz, 1H), 8.44(t, J=7.6 Hz,1H), 8.35–7.98(m, 2H), 7.97(s, 1H), 7.86(d, J=8.8 Hz, 2H), 7.61–7.55(m,2H), 7.38–7.31(m, 4H), 7.31–7.24(m, 1H), 7.07(d, J=8.8 Hz, 2H), 6.82(d,J=5.6 Hz, 1H), 4.51(t, J=6.0 Hz, 2H), 3.83(s, 2H), 3.52(t, J=6.0 Hz,2H). 163e 126

N-(3-Fluoro-4-(2-(4-(3- morpholinopropoxy)phenyl)-thieno[3,2-b]pyridin-7-yloxy) phenylcarbamothioyl)-2- phenylacetamide ¹HNMR (400 MHz, DMSO-d₆) δppm: 12.46(s, 1H), 11.82(s, 1H), 8.48(d, 1H,J=5.3 Hz), 8.00(d, 1H, J=12.5 Hz), 7.91(s, 1H), 7.80(d, 2H, J=8.8 Hz),7.53 (m, 2H), 7.34–7.22(m, 5H), 7.04(d, 2H, J=8.6 Hz), 6.61(d, 1H, J=5.7Hz), 4.10–4.07(m, 2H), 3.83(s, 2H), 3.59–3.55(m, 4H), 2.50– 2.41(m, 6H),1.92(m, 2H) 163f 127

tert-Butyl 2-(4-(7-(2-fluoro-4- (3-(2-phenylacetyl)thioureido)phenoxy)thieno[3,2-b]pyridin- 2-yl)phenoxy)ethyl(methyl) carbamate ¹HNMR(400 MHz, DMSO-d₆) δ ppm: 12.50(S, 1H), 11.85(s, 1H), 8.50(d, 1H,J=5.5 Hz), 8.02(d, 1H, J=13.3 Hz), 7.94(s, 1H), 7.83(d, 2H, J=8.8 Hz),7.55–7.54(m, 2H), 7.38–7.26(m, 5H), 7.08(d, 2H, J=8.8 Hz), 6.63(d, 1H,J=5.3 Hz), 4.17(br s, 2H), 3.83(s, 2H), 3.56(m, 2H), 2.90–2.86(m, 3H),1.40–1.36(m, 9H). 163g 128

N-(3-Fluoro-4-(2-(3-methoxy- 4-(2-morpholinoethoxy)phenyl)thieno[3,2-b]pyridin-7- yloxy)phenylcarbamothioyl)-2-phenylacetamide ¹H NMR(400 MHz, DMSO-d₆) δ ppm: 8.51(d, 1H, J=5.5 Hz),8.03–8.01(m, 2H), 7.55–7.53(m, 2H), 7.47(d, 1H, J=2.2 Hz), 7.39–7.24(m,6H), 7.10(d, 1H, J=8.6 Hz), 6.63(d, 1H, J=5.5 Hz), 4.14(t, 2H, J=5.9Hz), 3.88(s, 3H), 3.83(s, 2H), 3.58(t, 4H, J=4.6 Hz), 2.71(t, 2H, J=5.9Hz), 2.46–2.43(m, 4H). 163h 129

N-(3-Fluoro-4-(2-(2-(2- morpholinoethoxy)phenyl)thieno[3,2-b]pyridin-7-yloxy) phenylcarbamothioyl)-2- phenylacetamidehydrochloride ¹H NMR(400 MHz, DMSO-d₆) δ ppm: ppm: 12.50(s, 1H),11.86(s, 1H), 11.66– 11.50(brs, 1H), 8.79–8.76(m, 1H), 8.37(d, 1H, J=5.9Hz), 8.08(dd, 1H, J=11.3/2.0 Hz), 7.93(dd, 1H, J=7.6/1.6 Hz), 7.63–7.52(m, 3H), 7.35–7.16(m, 7H), 6.99(t, 1H, J=4.8 Hz), 4.71(br s, 2H),3.93– 3.91(m, 2H), 3.84(s, 2H), 3.80–3.77(m, 4H), 3.53–3.50(m, 2H),3.36–3.33(m, 2H).

Example 130N-(3-Fluoro-4-(2-(4-(piperidin-4-ylmethoxy)phenyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(167a) Step 1.tert-Butyl-4-((4-(7-(2-fluoro-4-nitrophenoxy)thieno[3,2-b]pyridin-2-yl)phenoxy)methyl)piperidine-1-carboxylate(164)

Starting from the compound 153 (shown in the scheme 28) and followingthe procedure described above for the synthesis of compound 161 (step 2,scheme 31, example 122), title compound 164 was obtained in 69% yield.LRMS (M+1) 579.2 (100%).

Step 2. tert-Butyl4-((4-(7-(4-amino-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)phenoxy)methyl)piperidine-1-carboxylate(165)

Following the procedure described above for the synthesis of amine 157(scheme 30, example 121) but substituting nitro compound 156 for thenitro compound 164, title compound 165 was obtained in 99% yield (crudematerial, used in the next step without additional purification). LRMS(M+1) 549.2 (100%).

Step 3.tert-Butyl-4-((4-(7-(2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)thieno[3,2-b]pyridin-2-yl)phenoxy)methyl)piperidine-1-carboxylate(166)

Following the procedure described above for the synthesis of compound158 (scheme 30, example 121) but substituting amino compound 157 for theamino compound 165, title compound 166 was obtained in 31% yield. LRMS(M+1) 726.2 (100%).

Step 4.N-(3-Fluoro-4-(2-(4-(piperidin-4-ylmethoxy)phenyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamidedi-hydrochloride (167a)

Following the procedure described above for the synthesis of compound159 (scheme 30, example 121) but substituting Boc-protected aminocompound 158 for the Boc-protected amino compound 166, title compound167a (presumably as a di-hydrochloride salt) was obtained in 15% yield.Characterization of 167a is provided in the table 16. LRMS (M+1) 626.2(100%).

Example 131-132(S)—N-(3-Fluoro-4-(2-(4-(pyrrolidin-2-ylmethoxy)phenyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(167b) andN-(4-(2-(4-(4-Aminobutoxy)phenyl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenylcarbamothioyl)-2-phenylacetamide(167c)

Following the procedures described above for the synthesis of 167a(scheme 32, example 130) but replacing in the first step tert-butyl4-(hydroxymethyl)piperidine-1-carboxylate with (S)-tert-butyl2-(hydroxymethyl)pyrrolidine-1-carboxylate or tert-butyl4-hydroxybutylcarbamate, title compounds 167b-c were obtained.Characterization of 167b-c is provided in the table 16.

TABLE 16

167a–c: Examples 130–132 Characterization of compounds 167a–c (examples130–132) Cpd Ex X Name Characterization 167a 130

N-(3-Fluoro-4-(2-(4-(piperidin-4- ylmethoxy)phenyl)thieno[3,2-b]pyridin-7-yloxy)phenyl- carbamothioyl)-2-phenylacetamidedi-hydrochloride ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 8.41(d, J=5.6 hz, 1H),8.06(dd, J=3.2 and 12.4 Hz, 1H), 7.75(d, J=8.8 Hz, 2H), 7.65(s, 1H),7.37–7.43(m, 1H), 7.39(d, J=8.4 Hz, 1H), 7.37–7.33(m, 4H), 7.33– 7.25(m,1H), 7.04(d, J=8.8 Hz, 2H), 6.64(d, J=5.6 Hz, 1H), 3.98(d, J=5.6 Hz,2H), 3.76(s, 2H), 3.50–3.42(m, 2H), 3.12– 3.01(m, 2H), 2.25–2.16(m, 1H),2.162.06(m, 2H), 1.92–1.58(m, 2H). 167b 131

(S)-N-(3-Fluoro-4-(2-(4- (pyrrolidin-2-ylmethoxy)phenyl)thieno[3,2-b]pyridin-7-yloxy) phenylcarbamothioyl)-2- phenylacetamidedi-hydrochloride ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 12.46(s, 1H), 11.82(s,1H), 8.49(d, J=5.6 Hz, 1H), 8.04–7.88(m, 1H), 7.96(s, 1H), 7.86(d, J=8.8Hz, 1H), 7.56–7.51(m, 2H), 7.36–7.31(m, 4H), 7.31–7.24(m, 1H), 7.11(d,J=8.8 Hz, 2H), 6.63(d, J=5.6 Hz, 1H), 4.34(dd, J=4.4 and 10.8 Hz, 1H),4.20–4.12(m, 1H), 4.00–3.90(m, 1H), 3.82(s, 2H), 3.28–3.18(m, 2H), 2.20–2.10(m, 1H), 2.05–1.88(m, 2H), 1.82– 1.70(m, 1H). 167c 132 —O(CH₂)₄NH₂N-(4-(2-(4-(4-Aminobutoxy) ¹H NMR (400 MHz, DMSO-d₆) δ ppm:phenyl)thieno[3,2-b]pyridin-7- 8.40(d, J=5.6 Hz, 1H), 8.05(dd, J=3.2 andyloxy)-3-fluorophenylcarbamothioyl)- 12.0 Hz, 1H), 7.75(d, J=8.8 Hz,2H), 2-phenylacetamide di-hydrochioride 7.64(s, H), 7.48–7.43(m, 1H),7.39(d, J= 8.8 Hz, 1H), 7.37–7.31(m, 4H), 7.31– 7.24(m, 1H), 7.03(d,J=8.8 Hz, 2H), 6.64(d, j=5.6 Hz, 1H), 4.11(t, J=5.6 Hz, 2H), 3.76(s,2H), 3.03(t, J=7.2 Hz, 2H), 1.99–1.83(m, 4H).

Example 133N-(3-Fluoro-4-(thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(170a) Step 1. 7-(2-Fluoro-4-nitrophenoxy)thieno[3,2-b]pyridine (168)

Starting from the chloride 2 (scheme 1) and following the proceduredescribed above for the synthesis of compound 6 (scheme 1, example 1),title compound 168 was obtained in 45% yield. LRMS (M+1) 290.3 (100%).

Step. 3-Fluoro-4-(thieno[3,2-b]pyridin-7-yloxy)benzenamine (169)

Starting from the nitro compound 168 and following the proceduredescribed above for the synthesis of amine 49 (scheme 10, example 55),title compound 169 was obtained in 41% yield. LRMS (M+1) 260.3 (100%).

Step 3.N-(3-Fluoro-4-(thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(170a)

Starting from the amine 169 and following the procedure described abovefor the synthesis of compound 50 (scheme 10, example 55), title compound170a was obtained in 29% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 12.46(s, 1H), 11.81 (s, 1H), 8.52(d, J=5.2 Hz, 1H), 8.17(d, J=5.2 Hz, 1H),8.01(dd, J=2.0 and 11.2 Hz, 1H), 7.60(d, J=5.2 Hz, 1H), 7.58-7.48 (m,2H), 7.36-7.30 (m, 4H), 7.30-7.22 (m, 1H), 6.64(d, J=5.2 Hz, 1H), 3.82(s, 2H). LRMS (M+1) 437.5 (100%).

Example 134N-(2-Chloro-4-(thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(170b)

Title compound 170b (example 134) was obtained according to the scheme33 via a 3-step synthesis starting from the chloride 2 and replacing2-fluoro-4-nitrophenol [in the step 1] with 3-chloro-4-nitrophenol. ¹HNMR (400 MHz, DMSO-d₆) δ ppm: 12.36(s, H), 11.88(s, 1H), 8.55(d, J=5.6Hz, 1H), 8.159d, J=5.6 Hz, 1H), 8.08(d, J=8.8 Hz, 1H), 7.61(d, J=2.8 Hz,1H), 7.60(d, J=5.6 Hz, 1H), 7.36-7.30 (m, 4H), 7.32(m, J=2.8 Hz, 1H),7.30-7.24 (m, 1H), 6.73(d, J=5.6 Hz, 1H), 3.84 (s, 2H).

Example 135N-(2-Chloro-4-(thieno[3,2-d]pyrimidin-4-yloxy)phenylcarbamothioyl)-2-phenylacetamide(173) Step 1. 4-(3-Chloro-4-nitrophenoxy)thieno[3,2-d]pyrimidine (171)

Starting from the chloride 20 (scheme 4) and following the proceduredescribed above for the synthesis of compound 24 (scheme 4, example 22)replacing 2-fluoro-4-nitrophenol with 3-chloro-4-nitrophenol, titlecompound 171 was obtained in 72% yield. LRMS (M+1) 307.7 (100%).

Step 2. 2-Chloro-4-(thieno[3,2-d]pyrimidin-4-yloxy)benzenamine (172)

Starting from the nitro compound 171 and following the proceduredescribed above for the synthesis of amine 25 (scheme 4, example 22),title compound 172 was obtained in 80% yield. LRMS (M+1) 277.7 (100%).

Step 3.N-(2-Chloro-4-(thieno[3,2-d]pyrimidin-4-yloxy)phenylcarbamothioyl)-2-phenylacetamide(173)

Starting from the amine 172 and following the procedure described abovefor the synthesis of compound 26a (scheme 4, example 22), title compound173 was obtained in 9% yield. ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 12.35 (s,1H), 11.89 (s, 1H), 8.72 (s, 1H), 8.48(d, J=5.6 Hz, 1H), 8.04(d, J=8.8Hz, 1H), 7.69(d, J=2.8 Hz, 1H), 7.68(d, J=5.6 Hz, 1H), 7.40(dd, J=2.8and 8.8 Hz, 1H), 7.36-7.30 (m, 4H), 7.30-7.24 (m, 1H), 3.84 (s, 2H).LRMS (M+1) (100%).

Example 1362-Phenyl-N-(2-(thieno[3,2-d]pyrimidin-4-ylamino)pyrimidin-5-ylcarbamothioyl)acetamide(174)

Title compound 174 (example 136) was obtained according to the scheme 34via a 3-step synthesis starting from the chloride 20 and replacing3-chloro-4-nitrophenol [in the step 1] with 5-nitropyrimidin-2-amine. ¹HNMR (400 MHz, DMSO-d₆) δ ppm: 11.85(bs, 2H), 10.91(bs, 1H), 8.71 (s,1H), 8.64 (s, 2H), 8.63-8.61 (m, 1H), 8.25(d, J=5.6 Hz, 1H), 7.45(d,J=5.6 Hz, 1H), 7.34-7.27 (m, 4H), 7.27-7.21 (m, 1H), 3.79 (s, 2H).

Example 137N-(3-Fluoro-4-(2-(1-methyl-1H-imidazol-4-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-(2-fluorophenyl)acetamide(178) Step 1.7-Chloro-2-(1-methyl-1H-imidazol-4-yl)thieno[3,2-b]pyridine (175)

To a solution of chloride 2 (scheme 1) (2.45 g, 14.4 mmol) in THF (48mL) at −78° C. was slowly added n-BuLi (2.5M in hexane, 7.2 mL, 18.0mmol). The reaction mixture was stirred for one hour [at −78° C.]followed by slow addition of ZnCl (0.5M in THF, 36 mL, 18.0 mmol). In afew minutes the reaction mixture was allowed to warm to room temperatureand stirred for one hour.

A solution of 4-iodo-1-methyl-1H-imidazole (1.50 g, 7.2 mmol) [Tet.Lett. 2004, 45, 5529] in THF (5 mL) and thetetrakis(triphenylphosphine)palladium (0) (0.83 g, 0.72 mmol) were addedto the reaction mixture which was heated to reflux for 1 hour, cooled toroom temperature, diluted with aqueous ammonium hydroxide and, finallyneutralized with a 1N HCl solution. The acidic solution was extractedwith DCM, the extract was washed with water and brine, dried overanhydrous magnesium sulfate, filtered and evaporated under reducedpressure. The residue was purified by flash chromatography (eluents DCM,then DCM-MeOH, 97:3) to afford title compound 175 (1.45 g, 81% yield) asa yellow solid. LRMS (M+1) 263.9 (100%), 265.9 (33%).

Step 2.7-(2-Fluoro-4-nitrophenoxy)-2-(1-methyl-1H-imidazol-4-yl)thieno[3,2-b]pyridine(176)

Starting from the chloride 175 and following the procedure describedabove for the synthesis of compound 11 (scheme 2, example 12), titlecompound 176 was obtained in 47% yield. LRMS (M+1) 371.0 (100%).

Step 3.3-Fluoro-4-(2-(1-methyl-1H-imidazol-4-yl)thieno[3,2-b]pyridin-7-yloxy)benzenamine(177)

Starting from the nitro compound 176 and following the proceduredescribed above for the synthesis of amine 49 (scheme 10, example 55),title compound 177 was obtained in 74% yield. LRMS (M+1) 341.0 (100%).

Step 4.N-(3-Fluoro-4-(2-(1-methyl-1H-imidazol-4-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-(2-fluorophenyl)acetamide(178)

Starting from the amine 177, following the procedure described above forthe synthesis of compound 50 (scheme 10, example 55) but replacing2-phenylacetyl isothiocyanate with 2-(2-fluorophenyl)acetylisothiocyanate, title compound 178 was obtained in 24% yield. ¹H NMR(400 MHz, DMSO-d₆) δ ppm: 12.44 (s, 1H), 11.88 (s, 1H), 8.46 (d, 1H,J=5.5 Hz), 8.34 (dd, 1H, J=12.3/2.2 Hz), 7.87 (d, 1H, J=1.2 Hz), 7.72(d, 1H, J=1.2 Hz), 7.69 (s, 1H), 7.57-7.49 (m, 2H), 7.43-7.31 (m, 2H),7.23-7.15 (m, 2H), 6.59 (d, 1H, J=5.5 Hz), 3.94 (s, 2H), 3.73 (s, 3H).LRMS (M+1) 536.1 (100%).

Example 138N-(3-Fluoro-4-(2-(1-methyl-1H-imidazol-4-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-(2-methoxyphenyl)acetamide(179)

Starting from the amine 177, following the procedure described above forthe synthesis of compound 50 (scheme 10, example 55) but replacing2-phenylacetyl isothiocyanate with 2-(2-methoxyphenyl)acetylisothiocyanate, title compound 179 was obtained in 52% yield. ¹H NMR(400 MHz, DMSO-d₆) δ ppm: 12.58 (s, 1H), 11.75 (s, 1H), 8.46 (d, 1H,J=5.5 Hz), 8.72 (dd, 1H, J=12.3/2.2 Hz), 7.86 (d, 1H, J=1.2 Hz), 7.72(d, 1H, J=0.8 Hz), 7.70 (s, 1H), 7.57-7.49 (m, 2H), 7.30-7.23 (m, 2H),7.00 (d, 1H, J=7.8 Hz), 6.92 (dt, 1H, J=7.3/0.9 Hz), 6.58 (d, 1H, J=5.1Hz), 3.82 (s, 2H), 3.79 (s, 3H), 3.72 (s, 3H).

Example 139N-(3-Fluoro-4-(2-(1-(2-(methylamino)ethyl)-1H-pyrazol-4-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-(2-methoxyphenyl)acetamide(184) Step 1. tert-Butyl2-(4-(7-chlorothieno[3,2-b]pyridin-2-yl)-1H-pyrazol-1-yl)ethyl(methyl)carbamate(180)

Starting from the chloride 2 and following the procedure described abovefor the synthesis of 175 (scheme 35, example 138), but replacing4-iodo-1-methyl-1H-imidazole with tert-butyl2-(4-iodo-1H-pyrazol-1-yl)ethyl(methyl)carbamate, title compound 180 wasobtained in 75% yield. LRMS (M+1) 393.1 (100%).

Step 2. tert-Butyl2-(4-(7-(2-Fluoro-4-nitrophenoxy)thieno[3,2-b]pyridin-2-yl)-1H-pyrazol-1-yl)ethyl(methyl)carbamate(181)

Starting from the chloride 180 and following the procedure describedabove for the synthesis of compound 11 (scheme 2, example 12), titlecompound 181 was obtained in 37% yield. LRMS (M+1) 514.1 (100%).

Step 3. tert-Butyl2-(4-(7-(4-amino-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)-1H-pyrazol-1-yl)ethyl(methyl)carbamate(182)

Starting from the nitro compound 181 and following the proceduredescribed above for the synthesis of amine 49 (scheme 10, example 55),title compound 182 was obtained in 22% yield. LRMS (M+1) 484.2 (100%).

Step 4. tert-Butyl2-(4-(7-(2-fluoro-4-(3-(2-(2-methoxyphenyl)acetyl)thioureido)phenoxy)thieno[3,2-b]pyridin-2-yl)-1H-pyrazol-1-yl)ethyl(methyl)carbamate(183)

Starting from the amine 182, following the procedure described above forthe synthesis of compound 50 (scheme 10, example 55) but replacing2-phenylacetyl isothiocyanate with 2-(2-methoxyphenyl)acetylisothiocyanate, title compound 183 was obtained in 90% yield. LRMS (M+1)691.2 (100%).

Step 5.N-(3-Fluoro-4-(2-(1-(2-(methylamino)ethyl)-1H-pyrazol-4-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-(2-methoxyphenyl)acetamide(184)

Starting from the compound 183 and following the procedure describedabove for the synthesis of compound 159 (scheme 30, step 4, example121), title compound 184 was obtained in 66% yield. ¹H NMR (400 MHz,DMSO-d₆) δ ppm: 8.45(d, J=5.6 Hz, 1H), 8.33(s, 1H), 8.00 (s, 1H),7.85-7.75 (m, 1H), 7.69 (s, 1H), 7.39(t, J=8.4 Hz, 1H), 7.35-7.28 (m,1H), 7.28-7.22 (m, 1H), 7.22(d, J=7.6 Hz, 1H), 6.97(d, J=8.4 Hz, 1H),6.89(t, J=7.6 Hz, 1H), 6.57(d, J=5.6 Hz, 1H), 4.19(t, J=6.4 Hz, 2H),3.82 (s, 2H), 3.77 (s, 3H), 2.88(t, J=6.4 Hz, 2H), 2.28 (s, 3H).

Example 140N-(3-Fluoro-4-(2-(1-(2-morpholinoethyl)-1H-imidazol-4-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-(2-methoxyphenyl)acetamide(185)

Title compound 185 (example 140) was obtained following the proceduresdescribed above for compound 183 [according to the scheme 36] via a4-step synthesis starting from chloride 2 and replacing tert-butyl2-(4-iodo-1H-pyrazol-1-yl)ethyl(methyl)carbamate [in the step 1] with4-(2-(4-iodo-1H-imidazol-1-yl)ethyl)morpholine [Tet. Lett. 2004, 45,5529]. ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 12.56 (s, 1H), 11.75 (s, 1H),8.55(d, J=5.6 Hz, 1H), 8.50-8.20 (m, 1H), 7.93(d, J=1.2 Hz, 1H), 7.78(s, 1H), 7.60-7.55 (m, 2H), 7.35(d, J=1.2 Hz, 1H), 7.32-7.25 (m, 1H),7.23(dd, J=1.6 and 7.2 Hz, 1H), 7.00(d, J=7.6 Hz, 1H), 6.92(td, J=0.8and 7.6 Hz, 1H), 6.69(d, J=5.6 Hz, 1H), 4.35(t, J=6.0 Hz, 2H), 3.81 (s,2H), 3.78 (s, 3H), 3.48(t, J=4.4 Hz, 4H), 2.59(t, J=6.0 Hz, 2H), 2.35(t,J=4.4 Hz, 4H).

Example 141N-(3-Fluoro-4-(6-(1-hydroxy-2-methylpropyl)thieno[3,2-d]pyrimidin-4-yloxy)phenylcarbamothioyl)-2-phenylacetamide(190) Step 1. 4-Chloro-thieno[3,2-d]pyrimidine-6-carbaldehyde (186)

Starting from 4-chloro-thieno[3,2-d]pyrimidine (20, scheme 4) andfollowing procedure described above for the synthesis of aldehyde 14(scheme 3, step 1, example 20), title compound 186 was obtained in 84%yield. LRMS (M+1) 199.0 (100%).

Steps 2-3.1-[4-(2-Fluoro-4-nitro-phenoxy)-thieno[3,2-d]pyrimidin-6-yl]-ethanol(188)

Starting from the aldehyde 186 and following procedures described abovefor the synthesis of nitro compound 16 (scheme 3, steps 2-3, example20), title compound 188 was obtained [via the intermediate alcohol 187],in 25% yield. LRMS (M+1) 336.0 (100%).

Steps 3-4.N-(3-Fluoro-4-(6-(1-hydroxy-2-methylpropyl)thieno[3,2-d]pyrimidin-4-yloxy)phenylcarbamothioyl)-2-phenylacetamide(190)

Starting from the nitro compound 188 and following procedures describedabove for the synthesis of compound 18a (scheme 3, steps 4-5, example20), title compound 190 was obtained [via the intermediate amino alcohol189], in 24% yield. ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 12.42 (s, 1H),11.80 (s, 1H), 8.64 (s, 1H), 7.90(dd, J=2.0 and 12.0 Hz, 1H), 7.52(t,J=8.4 Hz, 1H), 7.48(d, J=0.8 Hz, 1H), 7.46(dd, J=2.0 and 8.4 Hz, 1H),7.36-7.31 (m, 4H), 7.31-7.24 (m, 1H), 6.15(d, 4.8 Hz, 1H), 4.82(td,J=0.8 and 5.2 Hz, 1H), 3.82 (s, 2H), 2.10-1.98 (m, 1H), 0.93(d, J=6.8Hz, 3H), 0.90(d, J=6.8 Hz, 3H).

Examples 142-148N-(3-Fluoro-4-(6-(pyrrolidine-1-carbonyl)thieno[3,2-d]pyrimidin-4-yloxy)phenylcarbamothioyl)-2-phenylacetamide(26f)N-(4-(2-(Azetidine-1-carbonyl)thieno[3,2-b]pyridine-7-yloxy)-3-fluorophenylcarbamothioyl)-2-phenylacetamidehydrochloride (26g)1-(4-(6-(N-Ethyl-N-methylcarbamoyl)thieno[3,2-d]pyrimidin-4-yloxy)-3-fluorophenyl)-3-(2-phenylacetyl)thiourea(26h)N,N-Diethyl-4-(2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)thieno[3,2-d]pyrimidine-6-carboxamide(26i)(R)—N-(3-Fluoro-4-(6-(2-(hydroxymethyl)pyrrolidine-1-carbonyl)thieno[3,2-d]pyrimidin-4-yloxy)phenylcarbamothioyl)-2-phenylacetamide(26j)(S)—N-(4-(6-(3-(tert-Butyldimethylsilyloxy)pyrrolidine-1-carbonyl)thieno[3,2-d]pyrimidin-4-yloxy)-3-fluorophenylcarbamothioyl)-2-phenylacetamide(26k) tert-Butyl1-(4-(2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)thieno[3,2-d]pyrimidine-6-carbonyl)pyrrolidin-3-ylcarbamate(26l)

Compounds 26f-l (examples 142-148) were obtained by following theprocedures described above for the compound 26a (example 22, scheme 4).Characterization of 26f-l is provided in the table 17.

TABLE 17

26f–l: Examples 142–148 Characterization of compounds 26f–l (examples142–148) Cpd Ex R Name Characterization 26f 142

N-(3-Fluoro-4-(6-(pyrrolidine-1- carbonyl)thieno[3,2-d]pyrimidin-4-yloxy)phenylcarbamothioyl)- 2-phenylacetamide ¹H NMR (400 MHz,DMSO-d₆) δ (ppm): 12.42(s, 1H), 11.79(s, 1H), 8.77(s, 1H), 8.11(s, 1H),7.92(dd, J=2.0 and 11.6 Hz, 1H), 7.54(t, J=8.4 Hz, 1H), 7.47(dd, J=2.0and 8.4 Hz, 1H), 7.36–7.31(m, 4H), 7.30– 7.32(m, 1H), 3.85(t, J=6.4 Hz,2H), 3.82(s, 2H), 3.55(t, J=6.4 Hz, 2H), 1.96(quin, J= 6.4 Hz, 2H),1.89(quin, J=6.4 Hz, 2H). 26g 143

N-(4-(2-(Azetidine-1-carbonyl) thieno[3,2-b]□yridine-7-yloxy)-3-fluorophenylcarbamothioyl)- 2-phenylacetamide hydrochloride ¹H NMR(400 MHz, DMSO-d₆) δ (ppm): 12.48(s, 1H), 11.82(s, 1H), 8.64(d, J=5.6Hz, 1H), 8.03(db, J=12.8 Hz, 1H), 7.91(s, 1H), 7.58–7.52(m, 2H),7.37–7.31(m, 4H), 7.30–7.24(m, 1H), 6.82(d, J=5.6 Hz, 1H), 4.62(t, J=7.2Hz, 2H), 4.11(t, J=7.2 Hz, 2H), 3.82(s, 2H), 2.35(quin, J=7.2 Hz, 2H).26h 144

1-(4-(6-(N-Ethyl-N-methyl- carbamoyl)thieno[3,2-d] pyrimidin-4-yloxy)-3-fluorophenyl)-3- (2-phenylacetyl)thiourea ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 12.44(s, 1H), 11.81(s, 1H), 8.77(s, 1H), 8.03(s, 1/2H), 7.93(dd,1H, J=11.9/2.3 Hz), 7.89(s, 1/2H), 7.54(t, 1H, J=8.5 Hz), 7.48(dd, 1H,J=8.8/2.2 Hz), 7.38–7.32(m, 4H), 7.30–7.25(m, 1H), 3.82(s, 2H), 3.52(m,2H), 3.23(s, 3/2H), 3.04(s, 3/2H), 1.19(m, 3H). 26i 145

N,N-Diethyl-4-(2-fluoro-4-(3-(2- phenylacetyl)thioureido)phenoxy)thieno[3,2-d]pyrimidine-6- carboxamide ¹H NMR(400 MHz, DMSO-d₆) δ (ppm):12.44(s, 1H), 11.80(s, 1H), 8.77(s, 1/3H), 8.77(s, 2/3H), 7.93(dd, 1H,J=2.2/11.9 Hz), 7.89(s, 1/3H), 7.89(s, 2/3H), 7.54(t, 1H, J=8.5 Hz),7.48(dd, 1H, J=1.8/8.3 Hz), 7.34–7.33(m, 4H), 7.29–7.26(m, 1H), 3.83(s,2H), 3.53–3.48(m, 4H), 1.21(m, 6H). 26j 146

®-N-(3-Fluoro-4-(6-(2-(hydroxy- methyl)pyrrolidine-1-carbonyl)thieno[3,2-d]pyrimidin-4-yloxy) phenylcarbamothioyl)-2- phenylacetamide¹H NMR(400 MHz, DMSO-d₆) δ (ppm): 12.41(s, 1H); 11.80(s, 1H); 8.77 (s,1H); 8.08(s, 1H); 7.92(d, J=11.6 Hz, 1H); 7.54(t, J=8.8 Hz, 1H);7.49–7.45(m, 1H); 7.34– 7.26(m, 5H); 4.84(t, J=4.4 Hz, 1H); 4.23–4.19(m, 1H); 3.91–3.78(m, 2H); 3.82(s, 2H); 3.62–3.51(m, 2H);2.07–1.87(m, 4H). 26k 147

(S)-N-(4-(6-(3-(tert-Butyldimethyl- silyloxy)pyrrolidine-1-carbonyl)thieno[3,2-d]pyrimidin-4-yloxy)- 3-fluorophenylcarbamothioyl)-2-phenylacetamide ¹H NMR(400 MHz, CDCl₃) δ (ppm): 12.5(s, 1H), 8.79(s,1H), 8.66(d, 1H, J=0.4 Hz), 8.03–7.91(m, 2H), 7.52–7.21(m, 6H),4.60–4.52(m, 1H), 4.07–3.67(m, 4H), 2.13– 1.97(m, 2H), 1.28–1.26(m, 2H),0.93– 0.89(m, 9H), 0.14–0.09(m, 6H). 26l 148

tert-Butyl 1-(4-(2-fluoro-4-(3-(2- phenylacetyl)thioureido)phenoxy)thieno[3,2-d]pyrimidine-6- carbonyl)pyrrolidin-3-ylcarbamate 1H NMR (400MHz, DMSO-d6) δ (ppm): 8.77(s, 1H), 8.09(s, 0.5H), 8.05(s, 0.5H),7.96–7.93(m, 0.5H), 7.93–7.90(m, 0.5H), 7.58–7.50(m, 1H), 7.50–7.46(m,1H), 7.38– 7.31(nm, 4H), 7.31–7.24(m, 1H), 3.82(s, 2H), 4.15–1.20(m,7H).

Example 149N-(4-(6-(3-Aminopyrrolidine-1-carbonyl)thieno[3,2-d]pyrimidin-4-yloxy)-3-fluorophenylcarbamothioyl)-2-phenylacetamidehydrochloride (191)

Following the procedure described above for the synthesis of compound159 (scheme 30, example 121) but substituting Boc-protected aminocompound 158 for the Boc-protected amino compound 26l, title compound191 was obtained in 40% yield. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 8.77(s, 1H), 8.12 (s, 0.5H), 8.06 (s, 0.5H), 7.92(dd, J=2.4 and 12.0 Hz,1H), 7.54(t, J=8.4 Hz, 1H), 7.48(dd, J=2.4 and 8.4 Hz, 1H), 7.36-7.31(m, 4H), 7.30-7.25 (m, 1H), 4.2-3.80 (m, 1H), 3.08 (s, 2H), 3.80-3.50(m, 4H), 2.10-1.98 (m, 1H), 1.82-1.64(m, 1H). LRMS (M+1) 550.6 (100%).

Example 1502-(2,6-Dichlorophenyl)-N-(3-fluoro-4-(thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)acetamide(192a)

Starting from the amine 169 (scheme 33), following the proceduresdescribed above for the synthesis of compound 170a (example 133) butreplacing 2-phenylacetyl isothiocyanate with2-(2,6-dichlorophenyl)acetyl isothiocyanate, title compound 192a wasobtained in 7% yield. Characterization of 192a is provided in table 18.

Example 151N-(3-Fluoro-4-(thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-(thiophen-2-yl)acetamide(192b)

Starting from the amine 169 (scheme 33), following the proceduresdescribed above for the synthesis of compound 170a (example 133) butreplacing 2-phenylacetyl isothiocyanate with 2-(thiophen-2-yl)acetylisothiocyanate, title compound 192b was obtained in 9% yield.Characterization of 192b is provided in table 18.

Example 1522-(2,6-Difluorophenyl)-N-(3-fluoro-4-(thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)acetamide(192c)

Starting from the amine 169 (scheme 33), following the proceduresdescribed above for the synthesis of compound 170a (example 133) butreplacing 2-phenylacetyl isothiocyanate with2-(2,6-difluorophenyl)acetyl isothiocyanate, title compound 192c wasobtained in 23% yield. Characterization of 192c is provided in table 18.

Example 153N-(3-Fluoro-4-(thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-1-phenylcyclopropanecarboxamide(192d)

Starting from the amine 169 (scheme 33), following the proceduresdescribed above for the synthesis of compound 170a (example 133) butreplacing 2-phenylacetyl isothiocyanate with1-phenylcyclopropanecarbonyl isothiocyanate, title compound 192d wasobtained in 41% yield. Characterization of 192d is provided in table 18.

Example 154N-(3-Fluoro-4-(thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylpropanamide(192e)

Starting from the amine 169 (scheme 33), following the proceduresdescribed above for the synthesis of compound 170a (example 133) butreplacing 2-phenylacetyl isothiocyanate with 3-methyl-2-phenylbutanoylisothiocyanate, title compound 192e was obtained in 49% yield.Characterization of 192e is provided in table 18.

Example 155N-(3-Fluoro-4-(thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-3-phenylpropanamide(192f)

Starting from the amine 169 (scheme 33), following the proceduresdescribed above for the synthesis of compound 170a (example 133) butreplacing 2-phenylacetyl isothiocyanate with 3-phenylpropanoylisothiocyanate, title compound 192f was obtained in 59% yield.Characterization of 192f is provided in table 18.

TABLE 18

192a–f: Examples 150–155 Characterization of compounds 192a–f (examples150–155) Cpd Ex R Name Characterization 192a 150

2-(2,6-Dichlorophenyl)-N-(3- fluoro-4-(thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl) acetamide ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 12.27(s, 1H), 12.01(s, 1H), 8.52(d, J=5.6 Hz, 1H), 8.35–8.00(m,J=12.0 Hz, 1H), 7.59(d, J=5.6 Hz, 1H), 7.58–7.47(m, 4H), 7.36(t, J=8.0Hz, 1H), 6.64(d, J=5.6 Hz, 1H), 4.21(s, 2H). 192b 151

N-(3-Fluoro-4-(thieno[3,2-b] pyridin-7-yloxy)phenyl-carbamothioyl)-2-(thiophen- 2-yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 12.37(s, 1H), 11.80(s, 1H), 8.52(d, J=5.6 Hz, 1H), 8.17(d, J=5.6Hz, 1H), 7.98(d, J=12.4 Hz, 1H), 7.60(d, J=5.6 Hz, 1H), 7.54–7.46(m,2H), 7.42(dd, J=1.6 and 5.2 Hz, H), 7.20–6.97(m, 2H), 6.64(d, J= 5.6 Hz,1H), 4.07(s, 2H). 192c 152

2-(2,6-Difluorophenyl)-N-(3- fluoro-4-(thieno[3,2-b]pyridin-7-yloxy)phenyl- carbamothioyl)acetamide ¹H NMR (400 MHz,DMSO-d₆) δ (ppm): 12.28(s, H), 11.93(s, 1H), 8.52(d, J=5.6 Hz, H),8.17(d, J=5.6 Hz, 1H), 8.03– 7.98(m, 1H), 7.60(d, J=5.6 Hz, 1H),7.57–7.48(m, 2H), 7.46–7.37(m, 1H), 7.12(t, J=7.6 Hz, 2H), 6.65(d, J=5.6Hz, 1H), 3.96(s, 2H). 192d 153

N-(3-Fluoro-4-(thieno[3,2-b] pyridin-7-yloxy)phenyl-carbamothioyl)-1-phenyl- cyclopropane carboxamide ¹H NMR (DMSO) δ (ppm):12.31(1H, s), 9.26(1H, s), 8.52(1H, d, J=5.28 Hz), 8.17(1H, d, J=5.28Hz), 7.96(1H, d, J= 11.93 Hz), 7.60(1H, d, J=5.28 Hz), 7.52– 7.31(7H,m), 6.64(1H, d, J=5.09 Hz), 1.62(2H, brd, J=1.96 Hz), 1.33(2H, brd,J=2.35 Hz). MS (m/z) 464.2 (M + H). 192e 154

N-(3-Fluoro-4-(thieno[3,2-b] pyridin-7-yloxy)phenyl-carbamothioyl)-2-phenyl- propanamide ¹H NMR (400 MHz, DMSO-d₆) δ ppm12.50(1H, s), 11.77(1H, s), 8.52(1H, d, J= 5.28 Hz), 8.16(1H, d, J=5.48Hz), 8.00(1H, d, J=11.74), 7.60(1H, d, J=5.48 Hz), 7.55–7.48(2H, m),7.41–7.33(5H, m), 6.63(d, J=5.48 Hz), 4.10(1H, q, J= 6.85 Hz), 1.44(3H,d, J=6.85 Hz). MS (m/z) 452.1 (M + H) 192f 155

N-(3-Fluoro-4-(thieno[3,2-b] pyridin-7-yloxy)phenyl- carbamothioyl)-3-phenylpropanamide ¹H NMR(400 MHz, DMSO-d₆) δ ppm 12.58(2, 1H), 11.62(s,1H), 8.53(1H, d, J= 5.48 Hz), 8.17(1H, d, J=5.28 Hz), 8.03(1H, d,J=11.35 Hz), 7.60(1H, d, J= 5.48 Hz), 7.53–7.52(2H, br), 7.31– 7.21(5H,m), 6.66(1H, d, J=5.28 Hz), 2.92–2.87(2H, m), 2.83–2.79(2H, m). MS (m/z)452.1 (M + H)

Example 1562-(2,6-Dichlorophenyl)-N-(3-fluoro-4-(2-(pyrrolidine-1-carbonyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)acetamide(195a) Step 1.(7-(2-Fluoro-4-nitrophenoxy)thieno[3,2-b]pyridin-2-yl)(pyrrolidin-1-yl)methanone(193)

Starting from(7-chlorothieno[3,2-b]pyridin-2-yl)(pyrrolidin-1-yl)methanone (139,scheme 26) and following the procedure described above for the synthesisof compound 6 (scheme 1, example 1), title compound 193 was obtained in(93% yield). LRMS (M+1) 387.4 (100%).

Step 2.(7-(4-Amino-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)(pyrrolidin-1-yl)methanone(194)

Starting from the nitro compound 193 and following the proceduresdescribed above for the synthesis of amine 7, (scheme 1, example 1)title compound 194 was obtained in 92% yield. LRMS (M+1) 357.4 (100%).

Step 3.2-(2,6-Dichlorophenyl)-N-(3-fluoro-4-(2-(pyrrolidine-1-carbonyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)acetamide(195a)

Starting from the amine 194 and following the procedure described abovefor the synthesis of compounds 50 (scheme 10), 170a (scheme 33) or192a-f (scheme 39), title compound 195a was obtained in 70% yield.Characterization of 195a is provided in table 19.

Examples 157-181 Compounds 195b-q

Compounds 195b-q (examples 157-181) were obtained starting from theamine 194, following the procedure described above for the synthesis ofcompound 195a and replacing 2-(2,6-difluorophenyl)acetyl isothiocyanatewith an appropriately substituted homologue. Characterization of 195b-qis provided in the table 19.

TABLE 19

195a–q: Examples 156–181 Characterization of compounds 195 a–q (examples156–181) Cpd Ex R Name Characterization 195a 156

2-(2,6-Dichlorophenyl)-N-(3- fluoro-4-(2-(pyrrolidine-1-carbonyl)thieno[3,2-b]pyridin- 7-yloxy)phenylcarbamothioyl) acetamidehydrochloride ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.29(s, 1H), 12.02(s,1H), 8.63(d, J=5.6 Hz, 1H), 8.08–8.02(m, 1H), 8.04(s, 1H), 7.62(m, 4H),7.36(dd, J=7.2 and 8.4 Hz, 1H), 6.80(d, J=5.6 Hz, 1H), 4.21(s, 2H),3.85(t, J=6.4 Hz, 2H), 3.54(t, J=6.4 Hz, 2H), 1.97(quint, J=6.4 Hz, 2H),1.88(quint, J=6.4 Hz, 2H). 195b 157

2-(2,6-Difluorophenyl)-N-(3- fluoro-4-(2-(pyrrolidine-1-carbonyl)thieno[3,2-b]pyridin- 7-yloxy)phenylcarbamothioyl) acetamidehydrochloride ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.29(s, 1H), 11.94(s,1H), 8.63(d, J=5.6 Hz, 1H), 8.07–8.01(m, 1H), 8.05(s, 1H), 7.60–7.51(m,2H), 7.46–7.37(m, 1H), 7.18–709(m, 2H), 6.80(d, J=5.6 Hz, 1H), 3.97(s,2H), 3.85(t, J=6.4 Hz, 2H), 3.54(t, J=6.4 Hz, 2H), 1.97(quin, J=6.4 Hz,2H), 1.89(quin, J=6.4 Hz, 2H). 195c 158

2-Cyclohexyl-N-(3-fluoro-4- (2-(pyrrolidine-1-carbonyl)thieno[3,2-b]pyridin-7-yloxy) phenylcarbamothioyl) acetamidehydrochloride ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.67(s, 1H), 11.55(s,1H), 8.65(d, J=5.6 Hz, 1H), 8.12–8.06(m, 1H), 8.06(s, 1H), 7.60–7.53(m,2H), 6.82(d, J=5.6 Hz, 1H), 3.86(t, J=6.4 Hz, 2H), 3.54(t, J=6.4 Hz,2H), 2.37(d, J=6.8 Hz, 2H), 1.97(quin, J=6.4 Hz, 2H), 1.89(quin, J=6.4Hz, 2H), 1.71–1.58(m, 6H), 1.30–1.08(m, 3H), 1.07–0.92(m, 2H). 195d 159

N-(3-Fluoro-4-(2-(pyrrolidine- 1-carbonyl)thieno[3,2-b]pyridin-7-yloxy)phenyl- carbamothioyl)-2- (4-methoxyphenyl)acetamidehydrochloride ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.50(s, 1H), 11.77(s,1H), 8.64(d, J=5.6 Hz, 1H), 8.07–8.01(m, 1H), 8.05(s, H), 7.58–7.53(m,2H), 7.28–7.22(m, 2H), 6.94–6.88(m, 2H), 6.81(d, J=5.6 Hz, 1H), 3.85(t,J=6.4 Hz, 2H), 3.73(s, 2H), 3.73(s, 3H), 3.54(t, J=6.4 Hz, 2H),1.97(quin, J=6.4 Hz, 2H0, 1.89(quin, J=6.4 Hz, 2H). 195e 160

2-(3-Chlorophenyl)-N-(3- fluoro-4-(2-(pyrrolidine-1-carbonyl)thieno[3,2-b]pyridin- 7-yloxy)phenylcarbamothioyl) acetamidehydrochloride ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.42(s, 1H), 11.83(s,1H), 8.65(d, J=5.6 Hz, 1H), 8.07–8.01(m, 1H), 8.05(s, 1H), 7.59–7.52(m,2H), 7.44–7.26(m, 4H), 6.82(d, J=5.6 Hz, 1H), 3.86(s, 2H), 3.85(t, J=6.4Hz, 2H), 3.54(t, J=6.4 Hz, 2H), 1.97(quin, J=6.4 Hz, 2H), 1.89(quin,J=6.4 Hz, 2H). 195f 161

N-(3-Fluoro-4-(2-(pyrrolidine- 1-carbonyl)thieno[3,2-b]pyridin-7-yloxy)phenyl- carbamothioyl)-2-(thiophen- 2-yl)acetamidehydrochloride ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.39(s, 1H), 11.82(s,1H), 8.65(d, J=5.6 Hz, 1H), 8.08–8.00(m, 1H), 8.05(s, 1H), 7.60–.7.55(m,2H), 7.46–7.42(m, 1H), 7.04–6.98(m, 2H), 6.83(d, J=5.6 Hz, 1H), 4.06(s,2H), 3.85(t, J=6.4 Hz, 2H), 3.54(t, J=6.4 Hz, 2H), 1.98(quin, J=6.4 Hz,2H), 1.89(quin, J=6.4 Hz, 2H). 195g 162

2-(2-Chloro-6-fluorophenyl)- N-(3-fluoro-4-(2-(pyrrolidine-1-carbonyl)thieno[3,2-b] pyridin-7-yloxy)phenyl- carbamothioyl)acetamidehydrochloride ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.30(s, 1H), 11.99(s,1H), 8.63(d, J=5.6 Hz, 1H), 8.08–8.01(m, 1H), 8.05(s, 1H), 7.60–7.51(m,2H), 7.44–7.36(m, 2H), 7.30–7.24(m, 1H), 6.80(d, J=5.6 Hz, 1H), 4.07(s,2H), 3.85(t, J=6.4 Hz, 2H), 3.54(t, J=6.4 Hz, 2H), 1.95(quin, J=6.4 Hz,2H), 1.89(quin, J=6.4 Hz, 2H). 195h 163

1-(2-Adamantan-1-yl-acetyl)- 3-{3-fluoro-4-[2-(pyrrolidine-1-carbonyl)-thieno[3,2-b] pyridin-7-yloxy]-phenyl}- thiourea ¹H NMR (400MHz, DMSO-d₆) δ (ppm): 12.75(s, 1H), 11.45(s, 1H), 8.67(d, J=5.6 Hz,1H), 8.12(d, J=12.4 Hz, 1H), 8.06(s, 1H), 7.62–7.53(m, 2H), 6.86(d,J=5.6 Hz, 1H), 3.85(t, J=6.4 Hz, 2H), 3.54(t, J=6.4 Hz, 2H), 2.26(s,2H), 2.02–1.92(m, 5H), 1.89(quin, J=6.4 Hz, 2H), 1.70–1.57(m, 12H). 195i164

2-Cyclopentyl-N-(3-fluoro-4- (2-(pyrrolidine-1-carbonyl)thieno[3,2-b]pyridin-7-yloxy) phenylcarbamothioyl) acetamidehydrochloride ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.66(s, 1H), 11.55(s,1H), 8.65(d, J=5.6 Hz, 1H), 8.10–8.03(m, 2H), 7.59–7.54(m, 2H), 6.82(d,J=5.6 Hz, 1H), 3.86(t, J=6.4 Hz, 2H), 3.54(t, J=6.4 Hz, 2H), 2.20(quin,J=7.6 Hz, 1H), 1.97(quin, J=6.4 Hz, 2H), 1.89(quin, J=6.4 Hz, 2H),1.83–1.71(m, 2H), 1.68–1.47(m, 4H), 1.26–1.12(m, 2H). 195j 165

N-(3-Fluoro-4-(2-(pyrrolidine- 1-carbonyl)thieno[3,2-b]pyridin-7-yloxy)phenyl- carbamothioyl)-2-(3,4,5-tri-methoxyphenyl)acetamide hydrochloride ¹H NMR (400 MHz, DMSO-d₆) δ (ppm):12.49(s, 1H), 11.76(s, 1H), 8.60(d, J=5.6 Hz, 1H), 8.07–8.01(m, 2H),7.58–7.54(m, 2H), 6.77(d, J=5.6 Hz, 1H), 6.65(s, 2H), 3.86(t, J=6.4 Hz,2H), 3.76(s, 6H), 3.74(s, 2H), 3.63(s, 3H), 3.54(t, J=6.4 Hz, 2H),1.97(quin, J=6.4 Hz, 2H), 1.89(quin, J=6.4 Hz, 2). 195k 166

Methyl 4-(2-(3-(3-fluoro-4-(2- (pyrrolidine-1-carbonyl)thieno[3,2-b]pyridin-7-yloxy) phenyl)thioureido)-2- oxoethyl)benzoatehydrochloride ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.41(s, 1H), 11.86(s,1H), 8.60(d, J=5.6 Hz, 1H), 8.04(s, 1H), 8.04–8.00(m, 1H), 7.93(d, J=8.0Hz, 2H), 7.58–7.50(m, 2H), 7.47(d, J=8.0 Hz, 2H), 6.76(d, J=5.6 Hz, 1H),3.94(s, 2H), 3.86(t, J=6.4 Hz, 2H), 3.84(s, H), 3.54(t, J=6.4 Hz, 2H),1.97(quin, J=6.4 Hz, 2H), 1.89(quin, J=64 Hz, 2H). 195l 167

(R)-2-(2,2-Dimethyl-5-oxo- 1,3-dioxolan-4-yl)-N-(3-fluoro-4-(2-(pyrrolidine-1- carbonyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamoyl) ethanethioamide hydrochloride ¹H NMR (400 MHz,DMSO-d₆) δ (ppm): 12.32(s, 1H), 11.73(s, 1H), 8.64(d, J=5.6 Hz, 1H),8.05(s, 1H), 8.04–8.00(m, 1H), 7.60–7.54(m, 2H), 6.81(d, J=5.6 Hz, 1H),4.93(t, J=4.4 Hz, 1H), 3.86(t, J=6.4 Hz, 2H), 3.54(t, J=6.4 Hz, 2H),3.16(dd, J=4.4 and 16.8 Hz, 1H), 2.99(dd, J=5.0 and 16.8 Hz, 1H),1.97(quin, J=6.4 Hz, 2H), 1.89(quin, J=6.4 Hz, 2H). 195m 168

N-(3-Fluoro-4-(2-(pyrrolidine- 1-carbonyl)thieno[3,2-b]pyridin-7-yloxy)phenyl- carbamothioyl)-2-(2- fluorophenyl)acetamidehydrochloride ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.42(s, 1H), 11.88(s,1H), 8.67(d, J=5.6 Hz, 1H), 8.08–8.02(m, 1H), 8.06(s, H), 7.60–7.52(m,2H), 7.43–7.30(m, 2H), 7.24–7.16(m, 2H), 6.85(d, J=5.6 Hz, 1H), 3.989s,2H), 3.85(t, J=6.4 Hz, 2H), 3.54(t, J=6.4 Hz, 2H), 1.97(quin, J=6.4 Hz,2H), 1.89(quin, J=6.4 Hz, 2H). 195n 169

N-(3-Fluoro-4-(2-(pyrrolidine- 1-carbonyl)thieno[3,2-b]pyridin-7-yloxy)phenyl carbamothioyl)-2-(tetrahydro-2H-pyran-4-yl)acetamide hydrochloride ¹H NMR (400 MHz, DMSO-d₆) δ (ppm):12.63(s, 1H), 11.59(s, 1H), 8.66(d, J=5.2 Hz, 1H), 8.11–8.02(m, 1H),8.06(s, 1H), 7.60–7.54(m, 2H), 6.84(d, J=5.2 Hz, 1H), 3.85(t, J=6.8 Hz,2H), 3.85–3.79(m, 2H), 3.54(t, J=6.8 Hz, 2H), 3.30(t, J=12.0 Hz, 2H),2.43(d, J=6.8 Hz, 2H), 2.20–1.95(m, 1H), 1.97(quin, J=6.8 Hz, 2H),1.89(quin, J=6.8 Hz, 2H), 1.61(d, J=12.8 Hz, 2H), 1.25(qd, J=4.0 and12.0 Hz, 2H). 195o 179

N-(3-Fluoro-4-(2-(pyrrolidine- 1-carbonyl)thieno[3,2-b]pyridin-7-yloxy)phenyl- carbamothioyl)-2-(2- methoxyphenyl)acetamidehydrochloride ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.55(s, 1H), 11.73(s,1H), 8.63(d, J=5.6 Hz, 1H), 8.10–8.04(m, 2H), 7.60–7.51(m, 2H), 7.26(td,J=1.6 and 8.0 Hz, 1H), 7.21(dd, J=1.6 and 7.6 Hz, 1H), 6.99(d, J=8.0 Hz,H), 6.90(ts, J=1.2 and 7.6 Hz, 1H), 6.80(d, J=5.6 Hz, 1H), 3.86(t, J=6.4Hz, 2H), 3.81(s, 2H), 3.78(s, 3H), 3.54(t, J=6.4 Hz, 2H), 1.97(quin,J=6.4 Hz, 2H), 1.89(quin, J=6.4 Hz, 2H). 195p 180

2-(2,5-Dimethoxyphenyl)-N- (3-fluoro-4-(2-(pyrrolidine-1-carbonyl)thieno[3,2-b]pyridin- 7-yloxy)phenylcarbamothioyl) acetamidehydrochloride ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.53(s, 1H), 11.71 (s,1H), 6.64(d, J=5.6 Hz, 1H)<8.10–8.04(m, 1H), 8.05(s, 1H), 7.60–7.52(m,2H), 6.93–6.78(m, 4H), 3.85(t, J=6.4 Hz, 2H), 3.78(s, 2H), 3.72(s, 3H),3.69(s, 3H), 3.54(t, J=6.4 Hz, 2H), 1.97(quin, J=6.4 Hz, 2H), 1.89(quin,J=6.4 Hz, 2H). 195q 181

2-(3,4-Dimethoxyphenyl)-N- (3-fluoro-4-(2-(pyrrolidine-1-carbonyl)thieno[3,2-b]pyridin- 7-yloxy)phenylcarbamothioyl) acetamidehydrochloride ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.51(s, 1H), 11.76(s,1H), 8.69(d, J=5.6 Hz, 1H), 8.08–8.02(m, 1H), 8.07(s, 1H), 7.61–7.54(m,2H), 6.98–6.82(m, 4H), 3.85(t, J=6.4 Hz, 2H), 3.78–3.70(m, 8H), 3.54(t,J=6.4 Hz, 2H), 1.97(quin, J=6.4 Hz, 2H), 1.89(quin, J=6.4 Hz, 2H).

Example 182N-(3-Fluoro-4-(2-(pyrrolidine-1-carbonyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-(2-hydroxyphenyl)acetamidehydrochloride (196a)

Starting from the compound 195o and following the procedure describedabove for the synthesis of compound 155k (scheme 29, example 119), titlecompound 196a was obtained in 62% yield. Characterization of 196a isprovided in table 20.

Example 1832-(2,5-Dihydroxyphenyl)-N-(3-fluoro-4-(2-(pyrrolidine-1-carbonyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)acetamidehydrochloride (196b)

Starting from the compound 195p and following the procedure describedabove for the synthesis of 196a, title compound 196b was obtained in 83%yield. Characterization of 196b is provided in table 20.

Example 1842-(3,4-Dihydroxyphenyl)-N-(3-fluoro-4-(2-(pyrrolidine-1-carbonyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)acetamide(196c)

Starting from the compound 195q and following the procedure describedabove for the synthesis of 196a, title compound 196c was obtained in 25%yield. Characterization of 196c is provided in table 20.

TABLE 20 Characterization of compounds 196a–c (examples 182–184) Cpd ExR Name Characterization 196a 182

N-(3-Fluoro-4-(2-(pyrrolidine-1- carbonyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2- (2-hydroxyphenyl)acetamide hydrochloride¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.60(s, 1H), 11.67(s, 1H), 9.63(bs,1H), 8.63(d, J=5.6 Hz, 1H), 8.09–8.00(m, H), 8.05(s, 1H), 7.60–7.50(m,2H), 7.13(d, J=7.6 Hz, 1H), 7.08(t, J=7.6 Hz, 1H), 6.83–6.77(m, 2H),6.74(t, J=7.6 Hz, 1H), 3.85(t, J=6.4 Hz, 2H), 3.76(s, 2H), 3.54(t, J=6.4Hz, 12H), 1.97(quin, J=6.4 Hz, 2H), 1.89(quin, J=6.4 Hz, 2H). 196b 183

2-(2,5-Dihydroxyphenyl)-N- (3-fluoro-4-(2-(pyrrolidine-1-carbonyl)thieno[3,2-b]pyridin-7- yloxy)phenylcarbamothioyl) acetamidehydrochloride ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.59(s, 1H), 11.59(s,1H), 8.60(d, J=5.6 Hz, 1H), 8.08–8.03(m, 1H), 8.04(s, 1H), 7.58–7.52(m,2H), 6.77(d, J=5.6 Hz, 1H), 6.60(d, J=8.4 Hz, 1H), 6.57(d, J=2.8 Hz,1H), 6.49(dd, J=2.8 and 8.4 Hz, 1H), 3.86(t, J=6.4 Hz, 2H), 3.54(t,j=6.54 Hz, 2H), 1.97(quin, J=6.4 Hz, 2H), 1.89(quin, J=6.4 Hz, 2H). 196c184

2-(3,4-Dihydroxyphenyl)-N-(3- fluoro-4-(2-(pyrrolidine-1-carbonyl)thieno[3,2-b]pyridin-7- yloxy)phenylcarbamothioyl) acetamide ¹HNMR (400 MHz, DMSO-d₆) δ (ppm): 8.53(d, J=5.6 Hz, 1H), 8.07(dd, J=2.4and 12.0 Hz, 1H), 7.94(s, 1H), 7.50–7.44(m, 1H), 7.40(t, J=8.4 Hz, 1H),6.82–6.71(m, 3H), 6.65(dd, J=2.4 and 8.4 Hz, 1H), 3.92(t, J=6.4 Hz, 2H),3.67(t, J=6.4 Hz, 1H), 3.59(s, 2H), 2.09(quin, J=6.4 Hz, 2H), 2.02(quin,J=6.4 Hz, 2H).

Example 185N-(4-(2-(4-Hydroxyphenyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(200) Step 1. 2-Bromo-7-(4-nitrophenoxy)thieno[3,2-b]pyridine (197)

Starting from the compound 41 (scheme 8) and following the proceduredescribed above for the synthesis of compound 42 (scheme 8) butreplacing 2-fluoro-4-nitrophenol for 4-nitrophenol, title compound 197was obtained in 48% yield. LRMS (M+1) 350.9 (100%). 352.9 (100%).

Step 2. 4-(7-(4-Nitrophenoxy)thieno[3,2-b]pyridin-2-yl)phenol (198)

Starting from the compound 197 and following the procedure describedabove for the synthesis of compound 153 (scheme 28), title compound 198was obtained in 81% yield. LRMS (M+1) 365.0 (100%).

Step 3. 4-(7-(4-Aminophenoxy)thieno[3,2-b]pyridin-2-yl)phenol (199)

Starting from the compound 198 and following the procedure describedabove for the synthesis of compound 154 (scheme 28), title compound 199was obtained in 83% yield. LRMS (M+1) 335.0 (100%).

Step 4.N-(4-(2-(4-Hydroxyphenyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(200)

Starting from the compound 199 and following the procedure describedabove for the compound 155a (scheme 28, example 109), title compound 200was obtained in 3% yield. ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 12.38 (s,1H), 11.74 (s, 1H), 9.94 (s, 1H), 8.46 (d, 1H, J=5.3 Hz), 7.81 (s, 1H),7.72 (d, 2H, J=9.0 Hz), 7.69 (dd, 2H, J=6.7/1.8 Hz), 7.34-7.27 (m, 7H),6.86 (dd, 2H, J=6.7/1.8 Hz), 6.61 (d, 1H, J=5.5 Hz), 3.82 (s, 2H). LRMS(M+1) 512.1 (100%).

Example 186N-(4-(2-(4-(2-Morpholinoethoxy)phenyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(203) Step 1.4-(2-(4-(7-(4-Nitrophenoxy)thieno[3,2-b]pyridin-2-yl)phenoxy)ethyl)morpholine(201)

Starting from the compound 198 (scheme 42) and following the proceduredescribed above for the compound 161 (scheme 31), title compound 201 wasobtained in 69% yield. LRMS (M+1) 478.1 (100%).

Step 2.4-(2-(4-(2-Morpholinoethoxy)phenyl)thieno[3,2-b]pyridin-7-yloxy)benzenamine(202)

Starting from the compound 201 and following the procedure describedabove for the compound 162 (scheme 31), title compound 202 was obtainedin 69% yield. LRMS (M+1) 448.2 (100%).

Step 3.N-(4-(2-(4-(2-Morpholinoethoxy)phenyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(203)

Starting from the compound 202 and following the procedure describedabove for the compound 163a (scheme 31), title compound 203 was obtainedin 30% yield. ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 12.38 (s, 1H), 11.73 (s,1H), 8.47 (d, 1H, J=5.5 Hz), 7.90 (s, 1H), 7.79 (s, 2H, J=9.0), 7.36 (d,2H, J=9.0 Hz), 7.43-7.27 (m, 7H), 7.05 (d, 2H, J=9.0 Hz), 6.63 (d, 1H,J=5.3 Hz), 4.15 (t, 2H, J=5.6 Hz), 3.82 (s, 2H), 3.58 (t, 4H, J=4.6 Hz),2.71 (t, 2H, J=5.7 Hz), 2.51-2.46 (m, 4H). LRMS (M+1) 625.2 (100%).

Example 187N-(3-fluoro-4-(6-(pyrrolidine-1-carbonyl)thieno[2,3-d]pyrimidin-4-yloxy)phenylcarbamothioyl)-2-phenylacetamide(211) Step 1. 4-Chlorothieno[2,3-d]pyrimidine (205)

Starting from thieno[2,3-d]pyrimidin-4(3H)-one (204) [J. Med. Chem.,1999, 42, 26, 5437-5447, Bull. Soc. Chim. Fr., 1975, 587-591] andfollowing the procedure described above for the synthesis of compound 20(scheme 4, example 22), title compound 205 was obtained in 93% yield.LRMS (M+1) 169.1 (100%), 171.1 (32%).

Steps 2-4.(4-Chlorothieno[2,3-d]pyrimidin-6-yl)(pyrrolidin-1-yl)methanone (208)

Starting from the compound 205 and following the procedures describedabove for the synthesis of amide 5 (scheme 1, steps 2-4, example 1),title compound 208 was obtained [via intermediates 206 and 207], in 76%yield as dark-brown oil (crude material, was used for the next stepwithout additional purification). LRMS (M+1) 268.2 (100%).

Step 5.(4-(2-Fluoro-4-nitrophenoxy)thieno[2,3-d]pyrimidin-6-yl)(pyrrolidin-1-yl)methanone(209)

Starting from the compound 208 and following the procedures describedabove for the synthesis of nitro compound 6 (scheme 1, step 5, example1), title compound 209 was obtained in 24% yield. LRMS (M+1) 389.1(100%).

Step 6.(4-(4-Amino-2-fluorophenoxy)thieno[2,3-d]pyrimidin-6-yl)(pyrrolidin-1-yl)methanone(210)

Starting from the compound 209 and following the procedures describedabove for the synthesis of amine 7 (scheme 1, step 6, example 1), crudetitle compound 210 was obtained. It was purified by flashchromatography, eluents DCM followed by DCM-MeOH-Et₃N (97.75:2:0.25), toafford title compound 210 in 54% yield as a yellow solid. LRMS (M+1)359.1 (100%).

Step 7.N-(3-Fluoro-4-(6-(pyrrolidine-1-carbonyl)thieno[2,3-d]pyrimidin-4-yloxy)phenylcarbamothioyl)-2-phenylacetamide(211)

Starting from the compound 210 and following the procedures describedabove for the synthesis of compound 8a (scheme 1, step 7, example 1),crude title compound 211 was obtained. It was purified by flashchromatography, eluents DCM and DCM-MeOH-Et₃N (97.75:2:0.25) followed bytrituration with a mixture of MeOH-EtOAc, to afford title compound 211in 17% yield as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 12.43(s, 1H), 11.80 (s, 1H), 8.70 (s, 1H), 8.06 (s, 1H), 7.93 (d, 1H,J=11.7/2.3 Hz), 7.53-7.47 (m, 2H), 7.34-7.26 (m, 5H), 3.90 (t, 2H, J=6.7Hz), 3.83 (s, 2H), 3.55 (t, 2H, J=6.7 Hz), 1.99-1.85 (m, 4H). LRMS (M+1)536.2 (100%).

Example 1882-Phenyl-N-(4-(thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)acetamide(170c) Step 1. 7-(4-Nitrophenoxy)thieno[3,2-b]pyridine (212)

Staring from the chloride 2, following the procedure described above forthe synthesis of compound 6 (scheme 1, example 1) but substituting2-fluoro-4-nitrophenol for 4-nitrophenol, title compound 212 wasobtained in 89% yield. MS (m/z) 273.0 (M+H).

Step 2. 4-(Thieno[3,2-b]pyridin-7-yloxy)benzenamine (213)

Staring from the nitro compound 212, following the procedure describedabove for the synthesis of amine 49 (scheme 10, example 55), titlecompound 213 was obtained in 90% yield. MS (m/z) 243.1 (M+H).

Step 3.2-Phenyl-N-(4-(thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)acetamide(170c)

Staring from the amine 213, following the procedure described above forthe synthesis of compound 50 (scheme 10, example 55), title compound170c was obtained in 34% yield. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.35(1H, s), 11.69 (1H, s), 8.47 (1H, d, J=5.28 Hz), 8.10 (1H, d, J=5.28Hz), 7.70 (1H, s), 7.68 (1H, s), 7.54 (1H, d, J=5.28 Hz), 7.30-7.22 (7H,m), 6.61 (1H, d, J=5.28 Hz), 3.78 (2H, s). MS (m/z) 420.0 (M+H).

Example 1892-Phenyl-N-(4-(thieno[3,2-b]pyridin-7-yloxy)-2-(trifluoromethyl)phenylcarbamothioyl)acetamide(170d)

Title compound 170d was obtained according to the scheme 45 via athree-step synthesis starting from the chloride 2 and replacing4-nitrophenol [in the first step] with4-nitro-3-(trifluoromethyl)phenol. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm):12.29 (s, 1H), 11.99 (s, 1H), 8.56 (d, J=5.3 Hz, 1H), 8.17 (d, J=5.3 Hz,1H), 7.84 (d, J=8.6 Hz, 1H), 7.74 (d, J=2.7 Hz, 1H), 7.63 (m, 2H), 7.34(m, 4H), 7.26 (m, 2H), 6.75 (d, J=5.3 Hz, 1H), 3.85 (s, 1H). MS (m/z):488.3 (M+H).

Example 1902-Phenyl-N-(4-(thieno[3,2-b]pyridin-7-ylamino)phenylcarbamothioyl)acetamide(170e)

Title compound 170e was obtained according to the scheme 45 via athree-step synthesis starting from the chloride 2 and replacing4-nitrophenol [in the first step] with 4-nitrobenzenamine. ¹H NMR (400MHz, DMSO-d₆) δ (ppm) 12.39 (s, 1H), 11.72 (s, 1H), 8.97 (s, 1H), 8.35(d, J=5.1 Hz, 1H), 8.03 (d, J=5.5 Hz, 1H), 7.64 (d, J=8.4 Hz, 2H), 7.49(d, J=5.3 Hz, 1H), 7.38 (m, 4H), 7.32 (d, J=8.4 Hz, 3H), 6.94 (d, J=5.5Hz, 1H), 3.87 (s, 1H). MS (m/z): 419.2 (M+H).

Example 1912-Phenyl-N-(4-(thieno[3,2-b]pyridin-7-ylthio)phenylcarbamothioyl)acetamide(170f)

Title compound 170f was obtained according to the scheme 45 via athree-step synthesis starting from the chloride 2 and replacing4-nitrophenol [in the first step] with 4-nitrobenzenethiol. ¹H NMR (400MHz, DMSO-d₆) δ ppm 12.65 (1H, s), 11.91 (1H, s), 8.62 (1H, d, J=4.70Hz), 8.28 (1H, d, J=5.28 Hz), 8.01-7.90 (2H, m), 7.79-7.68 (5H, m), 7.23(1H, m), 3.95 (2H, m). MS (m/z) 436.0 (M+H)

Example 192N-(2-Methoxy-4-(thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(170g)

Title compound 170g was obtained according to the scheme 45 via athree-step synthesis starting from the chloride 2 and replacing4-nitrophenol [in the first step] with 3-methoxy-4-nitrophenol [Hodgson,C., J. Chem. Soc., 1929, 2778). ¹H NMR (DMSO) δ (ppm): 12.70 (1H, s),11.71 (1H, s), 8.63 (1H, d, J=8.80 Hz), 8.51 (1H, d, J=5.28 Hz), 8.14(1H, d, J=5.48 Hz), 7.50 (1H, dd, J=5.48, 0.78 Hz), 7.36-7.25 (5H, m),7.13 (1H, d, J=2.54 Hz), 6.89 (1H, dd, J=8.80, 2.54 Hz), 6.69 (1H, d,J=5.48 Hz), 3.82 (5H, s). MS (m/z) 449.55 (M+H).

Example 193N-(2-Methoxy-4-(2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(217) Step 1.7-Chloro-2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridine (214)

Starting from tributyltin compound 98 (scheme 19) and following theprocedure described above for the synthesis of compound 10 (scheme 2,step 2, example 12) but replacing 2-bromothiazole with2-bromo-1-methyl-1H-imidazole, title compound 214 was obtained in 95%yield. MS (m/z) 250.1 (100%), 252.1 (37%), (M+H).

Step 2.7-(3-Methoxy-4-nitrophenoxy)-2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridine(215)

Starting from compound 214, following the procedure described above forthe synthesis of compound 11 (scheme 2, step 3, example 12) butreplacing 2-fluoro-4-nitrophenol with 3-methoxy-4-nitrophenol [Hodgson,C., J. Chem. Soc., 1929, 2778], title compound 215 was obtained in 9%yield. MS (m/z) 383.1 (M+H).

Step 3.2-Methoxy-4-(2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)benzenamine(216)

Starting from compound 215 and following the procedure described abovefor the synthesis of compound 12 (scheme 2, step 4, example 12), titlecompound 216 was obtained in 100% yield. MS (m/z) 353.1 (M+H).

Step 4.N-(2-Methoxy-4-(2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(217)

Starting from compound 216 and following the procedure described abovefor the synthesis of compound 13a (scheme 2, step 5, example 12), titlecompound 217 was obtained in 48% yield. ¹H NMR (400 MHz, DMSO-d₆) δ ppm12.07 (1H, s), 11.59 (1H, s), 8.45 (1H, d, J=5.48 Hz), 7.91 (1H, d,J=8.80 Hz), 7.85 (1H, s), 7.41 (1H, s), 7.24-6.98 (8H, m), 6.66 (1H, d,J=5.67 Hz), 3.99 (3H, s), 3.78 (3H, s), 3.59 (2H, s). MS (m/z) 530.2(M+H).

Example 1942-Cyclohexyl-N-(3-fluoro-4-(2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)acetamide(220a) Step 1.7-(2-Fluoro-4-nitrophenoxy)-2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridine(218)

Starting from compound 214 (scheme 46) and following the proceduredescribed above for the synthesis of compound 11 (scheme 2, step 3,example 12), title compound 218 was obtained in 45% yield. MS (m/z)371.1 (M+H).

Step 2.3-Fluoro-4-(2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)benzenamine(219)

Starting from compound 218 and following the procedure described abovefor the synthesis of compound 12 (scheme 2, step 4, example 12), titlecompound 219 was obtained in 86% yield. MS (m/z) 341.1 (M+H).

Step 3:2-Cyclohexyl-N-(3-fluoro-4-(2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)acetamide(220a)

To a suspension of 219 (50 mg, 0.145 mmol) in THF (1.5 mL) was added2-cyclohexylacetyl isothiocyanate (40 mg, 0.22 mmol) [P. A. S. Smith andR. O. Kan. J. Org. Chem., 1964, 2261] and the reaction mixture wasstirred for 3 hours transferred onto a flash chromatography column andeluted with EtOAc-MeOH mixture (19:1), to afford title compound 220a(27.5 mg, 31% yield) as a light yellow solid. Characterization of 220ais provided in the table 21.

Example 1952-Cyclopentyl-N-(3-fluoro-4-(2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)acetamide(220b)

Title compound 220b was obtained similarly to the compound 220a from theamine 219 and 2-cyclopentylacetyl isothiocyanate [P. A. S. Smith and R.O. Kan. J. Org. Chem., 1964, 2261] in 47% yield. Characterization of220b is provided in the table 21.

Example 196N-(3-Fluoro-4-(2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-(2-oxopyrrolidin-1-yl)acetamide(220c)

Title compound 220c was obtained similarly to the compound 220a from theamine 219 and 2-(2-oxopyrrolidin-1-yl)acetyl isothiocyanate [preparedaccording to the reference P. A. S. Smith and R. O. Kan. J. Org. Chem.,1964, 2261] in 18% yield. Characterization of 220c is provided in thetable 21.

Example 197N-(3-Fluoro-4-(2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-(tetrahydro-2H-pyran-4-yl)acetamide(220d)

Title compound 220d was obtained similarly to the compound 220a from theamine 219 and 2-(tetrahydro-2H-pyran-4-yl)acetyl isothiocyanate[prepared according to the reference P. A. S. Smith and R. O. Kan. J.Org. Chem., 1964, 2261] in 15% yield. Characterization of 220d isprovided in the table 21.

Example 198N-(3-Fluoro-4-(2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)acetamide(220e)

Title compound 220f was obtained similarly to the compound 220a from theamine 219 and acetyl isothiocyanate in 28% yield. Characterization of220f is provided in the table 21.

Example 199 (R)-Methyl4-(3-(3-fluoro-4-(2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)thioureido)-2-hydroxy-4-oxobutanoate(220f)

To a suspension of 219 (60 mg, 0.186 mmol) in THF (1.9 mL) was added(R)-2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetyl isothiocyanate (60mg, 0,28 mmol) [P. A. S. Smith and R. O. Kan. J. Org. Chem., 1964,2261]. The reaction mixture was stirred for 3 hours, concentrated,purified by flash chromatography, eluent EtOAc-MeOH (19:1), to produce asolid material (29.5 mg) which was dissolved in MeOH, treated with HCl(1N in Et₂O, 0.1 mL) and the mixture was stirred for 10 min at roomtemperature. The solution was concentrated, and the residue was purifiedby preparative HPLC (Aquasil C18 column, gradient: 30% MeOH to 95% MeOHin water, 45 min), to afford title compound 220f (15 mg, 13% yield) as awhite solid. Characterization of 220f is provided in the table 21.

TABLE 21

220a–f: Examples 194–199 Characterization of compounds 220a–f (examples194–199) Cpd Ex R Name Characterization 220a 194

2-Cyclohexyl-N-(3-fluoro-4-(2- (1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy) phenylcarbamothioyl)acetamide ¹HNMR:(DMSO-d₆) δ (ppm): 12.68(s, 1H), 11.57(s, 1H), 8.72(d, 5.5 Hz, 1H),8.40(s, 1H), 8.1(m, 1H), 7.88(m, 1H), 7.75(s, 1H), 7.61(m, 2H), 6.90(d,J=5.5 Hz, 1H), 4.05(s, 3H), 2.37(d, J=6.8 Hz, H), 1.79–1.60(m, 6H),1.28–1.12(m, 3H), 1.02–0.94(m, 2H). MS (m/z): 524.3 (M + 1). 220b 195

2-Cyclopentyl-N-(3-fluoro-4- (2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy) phenylcarbamothioyl)acetamide ¹H NMR(DMSO-d₆) δ (ppm): 12.66(s, 1H), 11.55(s, 1H), 8.5(m, 1H), 8.06(d,J=12.5 Hz, 1H), 7.9(s, 1H), 7.55 (m, 2H), 7.41(s, 1H), 7.05(s, 1H),6.69(m, 1H), 4.0(s, 3H), 2.5(m, 2H), 2.2(m, 1H), 1.78(m, 2H),1.61–1.52(m, 4H), 1.18(m, 2H). MS (m/z): 510.2 (M + 1) 220c 196

N-(3-Fluoro-4-(2-(1-methyl-1H- imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl- carbamothioyl)-2-(2-oxopyrrolidin-1-yl)acetamide ¹NMR (DMSO-d₆) δ (ppm): 8.52 (d, J=5.4 Hz,1H), 7.98(m, 1H), 7.89(m, 1H), 7.46(m, 2H), 7.40(s, 1H), 7.04(m, 1H),6.68(d, J=5.3 Hz, 1H), 4.18(s, 2H), 3.99(s, 3H), 3.37(m, 2H), 2.27(m,2H), 2.0(m, 2H). MS (m/z): 525.3 (M + 1). 220d 197

N-(3-Fluoro-4-(2-(1-methyl- 1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl- carbamothioyl)-2-(tetrahydro-2H-pyran-4-yl)acetamide ¹H NMR (DMSO-d₆) δ (ppm): 8.53 (d, J=5.3 Hz,1H), 8.03(d, J=12.5 Hz, 1H), 7.89(s, 1H), 7.52(m, 2H), 7.41(m, 1H),7.04(m, 1H), 6.69(d, J=5.4 Hz, 1H), 3.99(s, 3H), 3.82(m, 2H), 3.59(m,1H), 3.3(m, 2H), 2.43(m, 2H), 1.76(m, 2H), 1.25(m, 2H). MS (m/z): 526.2(M + 1). 220e 198 CH₃ N-(3-Fluoro-4-(2-(1-methyl- ¹H NMR (DMSO-d₆) δ(ppm): 12.55(br, 1H-imidazol-2-yl)thieno[3,2-b] 1H), 11.52(br, 1H),8.53(m, 1H), 8.03(m, pyridin-7-yloxy)phenyl- 1H), 7.90(s, 1H), 7.52(m,2H), 7.41(s, carbamothioyl)acetamide 1H), 7.04(s, 1H), 6.69(m, 1H),4.00(s, 3H), 2.18(s, 2H). MS (m/z): 442.1 (M + 1). 220f 199

(R)-Methyl 4-(3-(3-fluoro-4-(2- (1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy) phenyl)thioureido)-2-hydroxy-4-oxobutanoate ¹H NMR(DMSO-d₆) δ (ppm): 8.55(d, J=5.5 Hz, 1H), 8.04(m,1H), 7.92(s, 1H), 7.55(m, 2H), 7.43(d, J=1 Hz, 1H), 7.06(d, J=1 Hz, 1H),6.70(dd, J=5.5 Hz, J=1 Hz, 1H), 4.48(dd, J=5.2 Hz, J=7.2 Hz, 1H), 4.0(s,3H), 3.67(s, 3H), 2.92(dd, J=5.2 Hz, J=15.5 Hz, 1H), 2.86(dd, J=7.4 Hz,J=15.5 Hz, 1H). MS (m/z): 530.2 (M + 1)

Example 200N-((3-Fluoro-4-(2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)(methyl)carbamothioyl)-2-phenylacetamide(223) Step 1:N-(3-Fluoro-4-(2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(13d) andN-(3-fluoro-4-(2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-2-phenylacetamide(221)

To a suspension of 219 (400 mg, 1.18 mmol) in THF (12 mL) was added2-2-phenylacetyl isothiocyanate (312 mg, 1.76 mmol) [P. A. S. Smith andR. O. Kan. J. Org. Chem., 1964, 2261], the reaction mixture was stirredfor 3 hours, transferred onto a flash chromatography column and elutedwith EtOAc/MeOH mixture (98:2), to afford title compounds 13d (example15, 254 mg, 42% yield) and 221 (96 mg, 17% yield).

Characterization of 13d (example 15) is provided in the table 2.Compound 221 is characterized by its mass-spectrum: MS (m/z): 459.1(M+1).

Step 2.3-Fluoro-N-methyl-4-(2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)benzenamine(222)

To a solution of 221 (274.8 mg, 0.6 mmol) in DMF (6 mL) NaH (60% inmineral oil, 36 mg, 0.9 mmol) was added in one portion at 0° C. and thereaction mixture was stirred for 1 h, followed by addition of MeI (0.037mL, 0.6 mmol). The reaction mixture was allowed to warm up to roomtemperature, stirred overnight, diluted with EtOAc, washed with water,dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. Theresidue was treated with 6N HCl (3 mL), and heated at 100° C. for 3 h,cooled to room temperature and partitioned between water and DCM.Aqueous phase was collected, basified with 1N NaOH to pH 11 andextracted with EtOAc. The extract was dried over anhydrous Na₂SO₄ andconcentrated. The residue was purified by flash chromatography (eluentEtOAc/MeOH, 9:1) to afford title compound 222 (102 mg, 46% yield) as asyrup. MS (m/z): 355.1 (M+1).

Step 3:N-((3-Fluoro-4-(2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)(methyl)carbamothioyl)-2-phenylacetamide(223)

To a suspension of the 222 (102 mg, 2.88 mmol) in THF (3 ml) was added2-phenylacetyl isothiocyanate (51 mg, 0.288 mmol). The reaction mixturewas stirred for 1 hr, transferred onto a chromatography column andeluted with a mixture EtOAc/MeOH (19:1) to afford title compound 223 (30mg, 20% yield) as a white solid. ¹HNMR: (DMSO-d₆) δ (ppm): 10.88 (s,1H), 8.51 (d, J=5.3 Hz, 1H), 7.91 (s, 1H), 7.41-7.18 (m, 6H), 7.04 (m,4H), 6.5 (d, J=5.3 Hz, 1H), 4.0 (s, 3H), 3.6 (s, 2H), 3.43 (s, 3H). MS(m/z): 532.3 (M+1).

Example 201N-(4-(2-(1-Methyl-1H-imidazol-4-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(227) Step 1:7-Chloro-2-(1-methyl-1H-imidazol-4-yl)thieno[3,2-b]pyridine (224)

Starting from the compound 98 (scheme 19), following the proceduredescribed above for the synthesis of compound 10 (scheme 2, step 2,example 12) but replacing 2-bromothiazole with4-bromo-1-methyl-1H-imidazole, title compound 224 was obtained in 29%yield. MS (m/z): 250.1 (100%), 252.1 (37%) (M+1).

Step 2:2-(1-Methyl-1H-imidazol-4-yl)-7-(4-nitrophenoxy)thieno[3,2-b]pyridine(225)

A mixture of 224 (950 mg, 3.81 mmol), 4-nitrophenol (795 mg, 5.72 mmol),K₂CO₃ (1.05 g, 7.62 mmol) and Ph₂O (5 mL) was stirred at 190° C. for 2 hin a sealed tube, cooled and treated with additional amount of4-nitrophenol (795 mg, 5.72 mmol). The mixture was stirred for anotherhour at the same conditions, cooled to room temperature and diluted withDCM. The DCM solution was extracted with 2N HCl; the aqueous phase wascollected, basified with concentrated ammonium hydroxide solution(pH˜11) and extracted with EtOAc. The extract was dried over anhydrousNa₂SO₄ and concentrated under reduced pressure to afford 225 (860 mg,64% yield) as an orange solid. MS (m/z): 353.1 (M+1).

Step 3:4-(2-(1-Methyl-1H-imidazol-4-yl)thieno[3,2-b]pyridin-7-yloxy)benzenamine(226)

To a solution of 225 (860 mg, 2.44 mmol) and NiCl₂×6H₂O (1.16 mg, 4.88mmol) in MeOH/THF (49/81 mL) NaBH₄ (278 mg, 7.32 mmol) was carefullyadded. The reaction mixture was stirred for 10 min, concentrated underreduced pressure and the residue was suspended in 10% HCl. Thesuspension was basified with concentrated NH₄OH solution (pH ˜11) andextracted with EtOAc.

The extract was dried over anhydrous Na₂SO₄ and concentrated underreduced pressure to produce a solid material. The aqueous phase (asuspension) was filtered; the precipitate was collected, washed withMeOH and dried under reduced pressure.

Both precipitate and the solid obtained from the organic phase, werecombined to afford title compound 226 (947.4 mg, crude) as a brown solidthat was used in the next step without further purification. MS (m/z):323.1 (M+1).

Step 4:N-(4-(2-(1-Methyl-1H-imidazol-4-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(227)

To a suspension of the 226 (385 mg, 0.99 mmol) in THF (10 mL) was added2-phenylacetyl isothiocyanate (263 mg, 1.49 mmol). The reaction mixturewas stirred for 1 hr, transferred onto a chromatography column andeluted with EtOAc/MeOH (9:1) producing a solid material which wasre-crystallized from MeCN to afford title compound 227 (74.3 mg, 15%yield) as a white solid. ¹HNMR: (DMSO-d₆) d(ppm): 12.39 (s, 1H), 11.73(s, 1H), 8.43 (d, J=5.3 Hz, 1H), 7.84 (s, 1H), 7.72 (m, 3H), 7.66 (s,1H), 7.34-7.27 (m, 7H), 6.69 (d, J=5.3 Hz, 1H), 3.82 (s, 2H), 3.72 (s,3H). MS (m/z): 500.1 (M+1).

Example 202N-(4-(2-(1-Methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(228)

Title compound 228 was obtained starting from the compound 214 (scheme46) and following the procedures described above for the synthesis ofcompound 227 (scheme 49, example 201). ¹H NMR (DMSO-d₆) δ (ppm): 12.42(s, 1H), 11.77 (s, 1H), 8.74 (m, 1H), 8.37 (m, 1H), 7.87-7.78 (m, 1H),7.70 (m, 1H), 7.42-7.20 (m, 7H), 6.90 (m, 1H), 4.05 (d, J=1 Hz, 3H),3.83 (s, 2H). MS (m/z): 500.3.

Example 2031-(4-(2-(Methylthio)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenyl)-3-(2-phenylacetyl)thiourea(232a) Step 1: 7-Chloro-2-(methylthio)thieno[3,2-b]pyridine (229)

To a solution of 2 (200 mg, 1.18 mmol) in dry THF (11 ml) at −78° C. wasadded n-BuLi (0.57 mL, 2.5M solution on hexane, 1.41 mmol) and theresultant brown precipitate was stirred for 10 minutes. Methyl disulfide(0.16 ml, 1.77 mmol) was added slowly, the mixture was stirred at −78°C. for 3 hours and partitioned between DCM and water. Organic phase wasseparated, dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure to afford title compound 229 (0.240 g, 94% yield,crude) as a yellow solid. MS (m/z): 216.1 (100%), 218.1 (39%) (M+1).

Step 2: 7-(2-Fluoro-4-nitrophenoxy)-2-(methylthio)thieno[3,2-b]pyridine(230)

To a suspension of 229 (100 mg, 0.463 mmol) in diphenyl ether (4 mL),was added 2-fluoro-4-nitrophenol (109 mg, 0.695 mmol) and sodiumcarbonate (147 mg, 1.39 mmol). The reaction mixture was heated at 200°C. overnight, cooled to room temperature, loaded onto a flashchromatography column and eluted with EtOAc/hexane (1:1) to afford titlecompound 230 (0.135 mg, 86% yield) as a yellow solid. MS (m/z): 337.0(M+1).

Step 3:4-(2-(Methylthio)thieno[3,2-b]pyridin-7-yloxy)-3-fluorobenzenamine (231)

To as solution of 230 (84 mg, 0.250 mmol) in acetic acid (5 mL) at 100°C., was added iron powder (0.069 g, 1.249 mmol). The reaction mixturewas allowed to stir for 5 minutes, filtered through a celite pad andconcentrated under reduced pressure. The residue was purified by columnchromatography, eluent DCM/MeOH (50:1), to afford title compound 231 (61mg, 80% yield) as yellow oil. MS (m/z): 307.1 (M+1).

Step 4:1-(4-(2-(Methylthio)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenyl)-3-(2-phenylacetyl)thiourea(232a)

To a suspension of 231 (61 mg) in THF (2 mL) was added 2-phenylacetylisothiocyanate (42 mg, 0.199 mmol). The reaction mixture was stirred for3 hours, concentrated under reduced pressure and the residue waspurified by column chromatography, eluent EtOAc/hexane (35:65), toproduce yellow oil. Purification of this material by preparative HPLC(column C-18 Aquasil, gradient: 60% MeOH to 95% MeOH) afforded titlecompound 232a (25 mg, 26% yield) as a cream solid. Characterization of232a is provided in the table 22.

Example 2041-(4-(2-(Butylthio)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenyl)-3-(2-phenylacetyl)thiourea(232b)

Starting from the compound 2, following procedures described above forthe synthesis of compound 232a (example 203, scheme 50) but replacingmethyl disulfide with n-butyl disulfide in the step 1, title compound232b was synthesized. Characterization of 232b is provided in the table22.

Example 2051-(4-(2-(Benzylthio)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenyl)-3-(2-phenylacetyl)thiourea(232c)

Starting from the compound 2, following procedures described above forthe synthesis of compound 232a (example 203, scheme 50) but replacingmethyl disulfide with benzyl disulfide in the step 1, title compound232c was synthesized. Characterization of 232c is provided in the table22.

Example 2061-(4-(2-(Pyridin-2-ylthio)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenyl)-3-(2-phenylacetyl)thiourea(232d)

Starting from the compound 2, following procedures described above forthe synthesis of compound 232a (example 203, scheme 50) but replacingmethyl disulfide with 2-pyridyl disulfide in the step 1, title compound232d was synthesized. Characterization of 232d is provided in the table22.

TABLE 22

232a–d: Examples 203–206 Characterization of compounds 232a–d (examples203–206) Cpd Ex R Name Characterization 232a 203 Me1-(4-(2-(Methylthio)thieno ¹HNMR: (DMSO-d6) δ (ppm): [3,2-b]pyridin-7-12.46(s, 1H), 11.81(s, 1H), 8.45(s, 1H), yloxy)-3-fluorophenyl)-3-7.99(d, J=12.5, 1H), 7.51(s, 1H), (2-phenylacetyl)thiourea 7.50(s, 1H),7.46(s, 1H), 7.34–7.30(m, 2H), 7.30–7.27(m, 3H), 6.61(d, J=5.5 Hz, 1H),3.82(s, 2H), 2.71(s, 3H). MS (m/z): 484.1. 232b 204 n-Bu1-(4-(2-(Butylthio)thieno ¹H NMR (DMSO-d₆) δ (ppm): 12.46(s,[3,2-b]pyridin-7- 1H), 11.81(s, 1H), 8.46(d, J=5.5 Hz, 1H),yloxy)-3-fluorophenyl)-3- 7.98(d, J=12.44 Hz, 1H), 7.54(s, 1H),(2-phenylacetyl)thiourea 7.53–7.47(m, 2H), 7.35–7.31(m, 4H),7.31–7.24(m, 1H), 6.60(d, J=5.5 Hz, 1H), 3.82(s, 2H), 3.13(t, J=7.24 Hz,2H), 1.64(q, J=7.43 Hz, 2H), 1.42(sextuplet, J=7.43 Hz, 2H), 0.90(t,J=7.24 Hz, 3H). MS (m/z): 526.2 232c 205

1-(4-(2-(Benzylthio)thieno [3,2-b]pyridin-7-yloxy)-3-fluorophenyl)-3-(2- phenylacetyl)thiourea ¹H NMR (DMSO-d₆) δ (ppm):12.46 (s, 1H), 11.81(s, 1H), 8.44(d, J=5.5 Hz, 1H), 7.98(d, J=11.83 Hz,1H), 7.52– 7.45(m, 3H), 7.38–7.22(m, 10H), 6.60(d, J=5.5 Hz, 1H),4.39(s, 2H), 3.82(s, 2H). MS (m/z): 560.2 232d 206

1-(4-(2-(Pyridin-2-ylthio) thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenyl)-3- (2-phenylacetyl)thiourea ¹H NMR (DMSO-d6) δ(ppm): 8.55(d, J=5.3 Hz, 1H), 8.45(d, J=3.91 Hz, 1H), 8.00–7.95(m, 2H),7.74(td, J=7.83 Hz; 1.76 Hz, 1H), 7.50(s, 2H), 7.35–7.23(m, 8H), 6.70(d,J=5.3 Hz, 1H), 3.82(s, 2H), 1.23(s, 1H). MS (m/z): 547.2

Example 2071-(4-(2-(Methylsulfinyl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenyl)-3-(2-phenylacetyl)thiourea(207) Step 1:7-(2-Fluoro-4-nitrophenoxy)-2-(methylsulfinyl)thieno[3,2-b]pyridine(233)

To a solution of 230 (400 mg, 1.189 mmol, scheme 50) in DCM (12 mL) at0° C. was added m-CPBA (77%, 272 mg, 1.189 mmol). The reaction mixturewas stirred at 0° C. for 30 minutes, water was added and the phases wereseparated. The organic phase was collected, washed with a 1% sodiumhydroxide solution, dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. The residue was purified by column chromatography,eluent DCM/MeOH (20:1), to afford title compound 233 (414 mg, 90% yield,crude), which was used in the next step without further purification. MS(m/z): 353.0 (M+1).

Step 2:4-(2-(Methylsulfinyl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorobenzenamine(234)

To as solution of 233 (400 mg, 1.135 mmol) in acetic acid (10 mL) at100° C., was added iron powder (317 mg, 5.675 mmol). The reactionmixture was stirred for 5 minutes, filtered through a celite pad andconcentrated under reduced pressure. The residue was purified by columnchromatography, eluent EtOAc/hexane (4:1), to afford title compound 234(0.285 g, 69% yield) as a yellow solid. MS (m/z): 323.0 (M+1).

Step 3:1-(4-(2-(Methylsulfinyl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenyl)-3-(2-phenylacetyl)thiourea(235)

To a suspension of 234 (280 mg, 0.868 mmol) in THF (8 mL) was added2-phenyl acetyl isothiocyanate (185 mg, 1.04 mmol). The reaction mixturewas stirred for 3 hours, concentrated; the solid residue washed withEt₂O and dried, to afford title compound 235 (229 mg, 53% yield) as awhite-rose solid. ¹HNMR: (DMSO-d6) δ (ppm): 12.41 (s, 1H), 11.75 (s,1H), 8.54(d, J=5.3 Hz, 1H), 7.98 (s, 1H), 7.96(d, J=13.5 Hz, 1H),7.48(d, J=5.0 Hz, 2H), 7.30-7.26(m, 2H), 7.26-7.18 (m, 3H), 6.69(d,J=5.5 Hz, 1H), 3.25 (s, 2H), 2.98 (s, 3H). MS (m/z): 500.1 (M+1).

Example 2081-(4-(2-(Methylsulfonyl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenyl)-3-(2-phenylacetyl)thiourea(238) Step 1:7-(2-Fluoro-4-nitrophenoxy)-2-(methylsulfonyl)thieno[3,2-b]pyridine(236)

To a solution of 233 (50 mg, 0.142 mmol) in DCM (2 mL), was added mCPBA(77%, 33 mg, 0.142 mmol) at 0° C. The mixture was stirred at 0° C. for 1hour, water was added and the phases were separated. The organic layerwas collected, washed with a 1% sodium hydroxide solution, dried overanhydrous Na₂SO₄ and concentrated under reduced pressure to afford titlecompound 236 (46 mg, 88% yield, crude) as a yellow solid which was usedin the next step without additional purification. MS (m/z): 369.0 (M+1).

Step 2:4-(2-(Methylsulfonyl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorobenzenamine(237)

To a solution of 236 (45 mg, 0.122 mmol) in acetic acid (4 mL) at 100°C., was added iron powder (34 mg, 0.611 mmol). The reaction mixture wasstirred for 5 minutes, filtered through a celite pad and concentratedunder reduced pressure to afford title compound 237 (20 mg, 48% yield,crude) as a yellow oil that was used in the next step without furtherpurification. MS (m/z): 339.0 (M+1).

Step 3.1-(4-(2-(Methylsulfonyl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenyl)-3-(2-phenylacetyl)thiourea(238)

To a suspension of 237 (20 mg, 0.059 mmol) in THF (10 mL) was added2-phenylacetyl isothiocyanate (26 mg, 0.146 mmol). The reaction mixturewas stirred for 2 hours, concentrated under reduced pressure and theresidue was purified by column chromatography, eluent EtOAc/MeOH (19:1),to afford a solid material that was dissolved in a minimum MeOH andprecipitated with hexane to afford title compound 238 (9.6 mg, 31%) as awhite solid. ¹HNMR: (DMSO-d₆) δ (ppm): 12.48 (s, 1H), 11.81 (s, 1H),8.69(d, J=5.5 Hz, 1H), 8.36 (s, 1H), 8.03(d, J=12.13 Hz, 1H), 7.55 (s,2H), 7.36-7.30 (m, 2H), 7.30-7.24 (m, 3H), 6.86(d, J=5.5 Hz, 1H), 3.83(s, 2H), 3.54 (s, 3H). MS (m/z): 516.2.

Example 209N-(3-Fluoro-4-(2-(furan-2-carbonyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(242) Step 1: (7-Chlorothieno[3,2-b]pyridin-2-yl)(furan-2-yl)methanone(239)

To a solution of 2 (100 mg, 0.589 mmol) in THF (6 mL) at −78° C., wasadded n-BuLi (2.5 M in hexane, 0.259 mL, 8.84 mmol) and the reactionmixture was stirred 15 minutes. 2-Furoyl chloride (0.087 mL, 0.884 mmol)was added drop wise; the mixture was stirred for additional 2 hours andpartitioned between DCM and water. The organic layer was separated,dried over anhydrous Na₂SO₄ and concentrated under reduced pressure toafford title compound 239 (35 mg, 23% yield, crude) as a yellow solid,that was used in the next step without additional purification. MS(m/z): 264.0 (100%), 266.0 (40%) (M+1).

Step 2:(7-(2-Fluoro-4-nitrobenzyl)thieno[3,2-b]pyridin-2-yl)(furan-2-yl)methanone(240)

To a suspension of 239 (35 mg, 0.133 mmol) in Ph₂O (2 mL) was added2-fluoro-4-nitrophenol (42 mg, 0.265 mmol) and K₂CO₃ (73 mg, 0.530mmol). The reaction mixture was heated at 180° C. in a sealed flask for60 hrs, cooled down to room temperature, loaded onto a flashchromatography column and eluted with EtOAc/hexane mixture (1:1), toafford title compound 240 (20 mg 39% yield) as a yellow solid. MS (m/z):385.1 (M+1).

Step 3:(7-(4-Amino-2-fluorobenzyl)thieno[3,2-b]pyridin-2-yl)(furan-2-yl)methanone(241)

To as solution of 240 (20 mg, 0.052 mmol) in acetic acid (2 mL) at 100°C., was added iron powder (15 mg, 0.260 mmol). The reaction mixture wasstirred for 3 minutes, filtered through a celite pad and concentratedunder reduced pressure. The residue was purified by flashchromatography, eluent EtOAc/hexane (3:7) to afford title compound 241(3.3 mg, 18% yield) as a yellow solid. MS (m/z): 355.1 (M+1).

Step 4:N-(3-Fluoro-4-(2-(furan-2-carbonyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(242)

To a solution of 241 (3.3 mg, 0.0093 mmol) in THF (1 mL) was added2-phenylacetyl isothiocyanate (2 mg, 0.011 mmol). The reaction mixturewas stirred for 3 hours, concentrated under reduced pressure andpurified by column chromatography, eluent EtOAc/hexane (20:80), followedby precipitation from a mixture acetone/hexane. Thus, title compound 242was obtained (2.2 mg, 44% yield) as a yellow solid. ¹HNMR: 1HNMR:(DMSO-d6) δ (ppm): 12.49 (s, 1H), 11.82 (s, 1H), 8.67(d, J=5.5 Hz, 1H),8.63 (s, 1H), 8.22(s, 1H), 8.03(d, J=13.1 Hz, 1H), 7.79(d, J=3.7 Hz,1H), 7.60-7.55 (m, 2H), 7.55-7.25 (m, 5H), 6.89-6.87 (m, 1H), 6.83(d,J=5.5 Hz, 1H), 3.82 (s, 2H). MS (m/z): 532.1 (M+1).

Example 210N-(3-Fluoro-4-(5-(methoxymethyl)-5H-pyrrolo[3,2-d]pyrimidin-4-yloxy)phenylcarbamothioyl)-2-phenylacetamide(246) Step 1. 4-(2-Fluoro-4-nitrophenoxy)-5H-pyrrolo[3,2-d]pyrimidine(243)

To a suspension of 27 (0.400 g, 2.60 mmol) [G. B. Evans, R. H. Furneaux,et. al J. Org. Chem., 2001, 66, 17, 5723-5730] in diphenylether (25 ml)was added 2-fluoro-4-nitrophenol (614 mg, 3.90 mmol) and HCl (2N inEt₂O) (0.19 ml, 3.90 mmol). The reaction mixture was heated at 120° C.for 4 hours, cooled to room temperature and concentrated under reducedpressure, to afford title compound 243 (610 mg, 86% yield) as a blacksolid. MS (m/z): 274.1 (M+1).

Step 2:4-(2-Fluoro-4-nitrophenoxy)-5-(methoxymethyl)-5H-pyrrolo[3,2-d]pyrimidine(244)

To a suspension of 243 (150 mg, 0.547 mmol in DMF (6 mL) was added NaH(66 mg, 1.64 mmol), and the reaction mixture was stirred at 0° C. for 1hour. Chloromethyl methyl ester (132 mg, 1.641 mmol) was added drop wiseand the mixture was stirred at room temperature over night. MeOH (2 mL)was added and the mixture was stirred for an additional hour andpartitioned between EtOAc and water. The organic phase was collected,dried over anhydrous sodium sulfate and concentrated under reducedpressure to afford title compound 244 (86 mg, 49% yield, crude) as anorange solid. MS (m/z): 319.1 (M+1).

Step 3:3-Fluoro-4-(5-(methoxymethyl)-5H-pyrrolo[3,2-d]pyrimidin-4-yloxy)benzenamine(245)

To as solution of 244 (85 mg, 0.267 mmol) in acetic acid (8 mL) at 100°C., was added iron powder (75 mg, 1.34 mmol). The reaction mixture wasstirred for 5 minutes, filtered through Celite® pad and concentrated todryness; the residue was purified by flash chromatography, eluentDCM/MeOH (30:1) to afford title compound 245 (18 mg, 23% yield) as anorange solid. MS (m/z): 289.1 (M+1).

Step 4:N-(3-Fluoro-4-(5-(methoxymethyl)-5H-pyrrolo[3,2-d]pyrimidin-4-yloxy)phenylcarbamothioyl)-2-phenylacetamide(246)

To a suspension of 245 (18 mg, 0.062 mmol) in THF (1 mL) was added2-phenylacetyl isothiocyanate (12 mg, 0.069 mmol). The reaction mixturewas stirred for 3 hours, concentrated under reduced pressure and theresidue was purified by flash chromatography, eluent hexane/EtOAc (3:2)followed by recrystallization (MeCN/water), and preparative HPLC(Aquasil C-18, gradient: 60% MeOH to 95% MeOH in water), to afford titlecompound 246 (9.2 mg, 33% yield) as a white solid. ¹HNMR: (CD₃OD) δ(ppm): 8.35 (s, 1H), 8.03 (d, J=12.4 Hz, 1H), 7.96(d, J=3.13 Hz, 1H),7.44-7.26 (m, 6H), 6.69 (d, J=3.13 Hz, 1H), 5.29 (quintuplet, J=6.65 Hz,1H), 3.75 (s, 2H), 3.60 (d, J=10.96 Hz, 3H), 1.63(d, J=6.65 Hz, 6H). MS(m/z): 464.16 (M+1).

Example 211N-(3-Fluoro-4-(5-isopropyl-5H-pyrrolo[3,2-d]pyrimidin-4-yloxy)phenylcarbamothioyl)-2-phenylacetamide(249) Step 1: 4-(5H-Pyrrolo[3,2-d]pyrimidin-4-yloxy)-3-fluorobenzenamine(247)

A solution of 243 (263 mg, 0.966 mmol, scheme 54) in MeOH (10 mL) andPdCl₂ (1.8 mg, 0.01 mmol) was stirred in the atmosphere of hydrogen for60 hrs. The reaction mixture was filtered and the filtrate wasconcentrated under reduced pressure. Water was added to the residue andthe aqueous solution was extracted with DCM. The extract was dried overanhydrous Na₂SO₄ and concentrated under reduced pressure, to affordtitle compound 247 (170 mg, 72% yield, crude) as a gray solid. MS (m/z):243.08 (M+1).

Step 2:3-Fluoro-4-(5-isopropyl-5H-pyrrolo[3,2-d]pyrimidin-4-yloxy)benzenamine(248)

To a suspension of 247 (80 mg, 0.327 mmol) in THF (4 mL), was added PPh₃(258 mg, 0.983 mmol), DEAD (0.155 ml, 0.983 mmol) and isopropanol (0.075ml, 0.983 mmol), and the reaction mixture was allowed to stir for 48hours. 3N HCl solution (1.0 mL) was added and the mixture was extractedwith DCM. Aqueous phase was collected, neutralized with NaOH 10% (pH˜11) and extracted with DCM. The organic phase was collected, dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theresidue was purified twice by column chromatography: eluentsEtOAc/hexane (3:7) and MeOH/DCM (1:20), to afford title compound 248 (19mg, 31% yield) as yellow solid. MS (m/z): 287.1 (M+1).

Step 3:N-(3-Fluoro-4-(5-isopropyl-5H-pyrrolo[3,2-d]pyrimidin-4-yloxy)phenylcarbamothioyl)-2-phenylacetamide(249)

To a suspension of 248 (10 mg, 0.035 mmol) in THF (1 mL) was added2-phenylacetyl isothiocyanate (0.007 mL, 0.038 mmol). The reactionmixture was stirred for 3 hours, concentrated under reduced pressure andthe residue was purified by flash chromatography, eluent EtOAc/hexane(1:1) and preparative HPLC (C-18 Aquasyl column, gradient: 60% to 95%MeOH in water, 45 min), to afford title compound 249 (4 mg, 26% yield)as a white solid. ¹HNMR: (CD₃OD) δ (ppm): 8.35 (s, 1H), 8.03 (d, J=12.4Hz, 1H), 7.96(d, J=3.13 Hz, 1H), 7.44-7.26 (m, 6H), 6.69 (d, J=3.13 Hz,1H), 5.29 (quintuplet, J=6.65 Hz, 1H), 3.75 (s, 2H), 3.60 (d, J=10.96Hz, 3H), 1.63(d, J=6.65 Hz, 6H). MS (m/z): 464.2 (M+1).

Example 212N-(4-(5H-Pyrrolo[3,2-d]pyrimidin-4-yloxy)-3-fluorophenylcarbamothioyl)-2-(2,6-dichlorophenyl)acetamide(250) Step 1:N-(4-(5H-pyrrolo[3,2-d]pyrimidin-4-yloxy)-3-fluorophenylcarbamothioyl)-2-(2,6-dichlorophenyl)acetamide(250)

To a solution of 247 (200 mg, 0.819 mmol, scheme 55) in THF (8.2 mL)2-(2,6-dichlorophenyl)acetyl isothiocyanate (302 mg, 1.33 mmol) wasadded. The mixture was stirred for 1 h at room temperature, transferredonto a flash chromatography column and eluted with EtOAc/hexane (1:1).The solid material obtained was triturated with diethyl ether, filteredand dried under reduced pressure, to afford title compound 250 (200 mg,0.408, 50% yield) as a light brown solid. ¹HNMR: (DMSO-d₆) δ (ppm) 12.69(s, 1H), 12.26 (s, 1H), 12.04 (s, 1H), 7.94 (m, 2H), 7.53 (m, 4H), 7.39(m, 1H), 6.72 (m, 1H), 4.22 (s, 2H). MS (m/z): 490.1 (100%, 492.1 (77%)(M+1).

Example 213N-(3-Fluoro-4-(6-phenyl-5H-pyrrolo[3,2-d]pyrimidin-4-yloxy)phenylcarbamothioyl)-2-phenylacetamide(255a) Step 1: 4-Chloro-6-(phenylethynyl)pyrimidin-5-amine (251)

Ethynylbenzene (0.092 mL, 0.92 mmol) was added to a solution of4,6-dichloropyrimidin-5-amine (100 mg, 0.61 mmol), Pd(PPh₃)₄ (140 mg,0.12 mmol), CuI (116 mg, 0.61 mmol) and DIPEA (0.5 mL, 3.05 mmol) in DME(6.1 mL). The reaction mixture was stirred in the dark over night atroom temperature, diluted with DCM, washed sequentially with diluteaqueous citric acid and water, dried over anhydrous Na₂SO₄ andconcentrated under reduce pressure. The residue was purified by flashchromatography, eluent EtOAc/hexane (1:3), to afford title compound 251(30.8 mg, 22% yield) as a yellow solid. MS (m/z): 230.1 (100.0%), 232.1(33%) (M+1).

Step 2: 4-Chloro-6-phenyl-5H-pyrrolo[3,2-d]pyrimidine (252)

To a solution of 251 (30.8 mg, 0.134 mmol) in NMP (1.4 mL) a suspensionof KH in mineral oil (35%, 31 mL, 0.268 mmol) was added in one portion.The mixture was stirred at room temperature overnight and partitionedbetween EtOAc and water. The organic phase was collected, dried overanhydrous Na₂SO₄ and concentrated. The residue was purified by flashchromatography, eluent EtOAc/hexane (1:2) to afford title compoundaffording 252 (22.7 mg, 74% yield). MS (m/z): 230.1 (100%) 232.1 (33%)(M+1).

Step 3: 4-(2-Fluoro-4-nitrophenoxy)-6-phenyl-5H-pyrrolo[3,2-d]pyrimidine(253)

A mixture of 252 (47.9 mg, 0.21 mmol), 4-nitrophenol (50 mg, 0.32 mmol),K₂CO₃ (58 mg, 0.42 mmol) and Ph₂O (4 mL) was stirred at 190° C.overnight in a sealed tube. The mixture was cooled down, more4-nitrophenol (50 mg, 0.32 mmol) was added and the mixture was stirredat 190° C. for additional 8 h. It was cooled again, transferred onto achromatography column and eluted sequentially with EtOAc/hexane (1:10)and EtOAc/hexane (1:3), to afford title compound 253 (71.4 mg, 97%yield) as a white foam. MS (m/z): 351.1 (M+1).

Step 4:3-Fluoro-4-(6-phenyl-5H-pyrrolo[3,2-d]pyrimidin-4-yloxy)benzenamine(254)

To a solution of 253 (71.4 mg, 0.21 mmol) in acetic acid (2.1 mL) at100° C., was added iron powder (59 mg, 1.05 mmol). The reaction mixturewas stirred for 5 minutes, filtered through a Celite® pad andconcentrated under reduced pressure. The residue was purified by columnchromatography, eluent EtOAc/hexane (2:1), to afford title compound 254(27.9 mg, 40% yield). MS (m/z): 321.1 (M+1).

Step 5:N-(3-Fluoro-4-(6-phenyl-5H-pyrrolo[3,2-d]pyrimidin-4-yloxy)phenylcarbamothioyl)-2-phenylacetamide(255a)

To a suspension of the 254 (26.8 mg, 0.84 mmol) in THF (1.6 ml) wasadded 2-phenylacetyl isothiocyanate (23 mg, 0.13 mmol). The mixture wasstirred for 1 hr transferred onto a chromatography column and elutedsequentially with EtOAc/MeOH (9:1) and EtOAc/hexane (1:1), to affordtitle compound 255a (30 mg, 72% yield) as a white solid. ¹HNMR:(DMSO-d₆) δ (ppm): 12.65 (s, 1H), 12.43 (s, 1H), 11.79 (s, 1H), 8.31 (s,1H), 8.06 (d, J=7.6 Hz, 2H), 7.91 (m, 1H), 7.52 (m, 4H), 7.43 (m, 1H),7.34, (m, 4H), 7.27 (m, 1H), 7.18 (m, 1H), 3.83 (s, 2H). MS (m/z): 498.2(M+1).

Example 214N-(3-Fluoro-4-(6-(pyridin-2-yl)-5H-pyrrolo[3,2-d]pyrimidin-4-yloxy)phenylcarbamothioyl)-2-phenylacetamide(255b)

Following the procedures described above for the synthesis of compound255a (example 213, scheme 57) but replacing ethynylbenzene in the step 1with 2-ethynylpyridine, title compound 255b was obtained. ¹H NMR(DMSO-d₆) δ (ppm): 12.85 (br, 1H), 12.65 (br, 1H), 11.75 (br, 1H), 8.71(m, 1H), 8.33 (s, 1H), 8.21 (d, J=8Hz, 1H), 7.96 (m, 1H), 7.89 (m, 1H),7.52-7.42 (m, 3H), 7.34-7.32 (m, 5H), 7.28 (m, 1H), 3.83 (s, 2H). MS(m/z): 499.2 (M+1).

Example 215N-(4-(2-(4-Methyl-1H-pyrazol-1-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide (258a) Step 1:2-(4-Methyl-1H-pyrazol-1-yl)-7-(4-nitrophenoxy)thieno[3,2-b]pyridine(256)

A mixture of 197 (300 mg, 0.86 mmol, scheme 42), 4-methyl-1H-pyrazole(69 mg, 0.86 mmol), CuI (16.4 mg, 0.086 mmol),trans-N¹,N²-dimethylcyclohexane-1,2-diamine (24.4 mg, 0.172 mmol) [J. C.Antilla, A. Klapars, et. al. JACS, 2002, 124, 11684-1688] and K₂CO₃ (238mg, 1.72 mmol) in toluene (1.7 mL) was stirred at room temperature in anatmosphere of nitrogen overnight, diluted with EtOAc (100 mL), filteredthrough a Celite® pad, and concentrated under reduced pressure. Theresidue was purified by flash chromatography with gradient elution withEtOAc/hexane (1:1) to EtOAc/hexane (2:1) to afford title compound 256(88.8 mg, 37% yield) as a white solid. MS (m/z): 352.06 (M+1).

Step 2:4-(2-(4-Methyl-1H-pyrazol-1-yl)thieno[3,2-b]pyridin-7-yloxy)benzenamine(257)

To a solution of 256 (168.4 mg, 0.478 mmol) and NiCl₂×6H₂O (226 mg,0.956 mmol) in MeOH/THF (10/10 mL) NaBH₄ (72 mg, 1.92 mmol) wascarefully added. The reaction mixture was stirred for 10 min,concentrated to dryness and the resultant solid was suspended in 10%HCl. The aqueous solution was basified (pH ˜11) with concentratedaqueous NH₄OH and extracted with EtOAc. The organic extract wascollected, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure, to afford title compound 257 (134.6 mg, 87% yield) as a whitesolid. MS (m/z): 322.09 (M+1).

Step 3:N-(4-(2-(4-Methyl-1H-pyrazol-1-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(258a)

To a suspension of the 257 (134.6 mg, 0.418 mmol) in THF (4.2 mL) wasadded 2-phenylacetyl isothiocyanate (111 mg, 0.627 mmol). The reactionmixture was stirred for 1 hr at room temperature, transferred onto achromatography column and eluted with a gradient of gradientEtOAc/hexane, 1:1 to 2:1, to provide a beige solid which was trituratedwith diethyl ether to afford title compound 258a (31 mg, 15% yield) as awhite solid. Characterization of 258a is provided in the table 23.

Example 216N-(4-(2-(1H-Pyrazol-1-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(258b)

Following the procedures described above for the synthesis of compound258a (example 215, scheme 58) but replacing 4-methyl-1H-pyrazole in thestep 1 with 1H-pyrazole, title compound 258b was obtained.Characterization of 258b is provided in the table 23.

Example 217N-(4-(2-(3,5-Dimethyl-1H-pyrazol-1-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(258c)

Following the procedures described above for the synthesis of compound258a (example 215, scheme 58) but replacing 4-methyl-1H-pyrazole in thestep 1 with 3,5-dimethyl-1H-pyrazole, title compound 258c was obtained.Characterization of 258c is provided in the table 23.

TABLE 23

258a–c: Examples 215–217 Characterization of compounds 258a–c (examples215–217) Cpd Ex R Name Characterization 258a 215

N-(4-(2-(4-Methyl-1H-pyrazol- 1-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2- phenylacetamide ¹HNMR: (DMSO-d₆) δ (ppm):12.42(br, 1H), 11.76(br, 1H), 8.5(m, 2H), 7.75(m, 2H), 7.65(s, 2H),7.32(m, 7H), 6.65(m, 1H), 3.83(s, 2H), 2.12(s, 3H). MS (m/z): 500.0 (M +1). 258b 216

N-(4-(2-(1H-Pyrazol-1-yl)thieno [3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2- phenylacetamide ¹H NMR (DMSO-d₆) δ (ppm):12.4(s, 1H), 11.73(s, 1H), 8.74(d, J=2.5 Hz, 1H), 8.45(d, J=5.7 Hz, 1H),7.87(s, 1H), 7.81(m, 1H), 7.74(d, J=8.8 Hz, 1H), 7.34–7.31(m, 7H),6.66(m, 2H), 3.82(s, 2H). MS (m/z): 486.1 258c 217

N-(4-(2-(3,5-Dimethyl-1H- pyrazol-1-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl- carbamothioyl)-2- phenylacetamide ¹H NMR(DMSO-d₆) δ (ppm): 12.44(s, 1H), 11.77(s, 1H), 8.6(d, J=5.8, 1H),7.78(m, 2H), 7.49(s, 1H), 7.38– 7.28(m, 7H), 6.80(d, J=5.8 Hz, 2H),6.27(s, 1H), 3.83(s, 2H), 2.59(s, 3H), 2.21(s, 3H). MS (m/z): 514.1

Example 218N-(4-(1H-Pyrrolo[2,3-c]pyridin-7-yloxy)-3-fluorophenylcarbamothioyl)-2-phenylacetamide(262a) Step 1. 7-Chloro-1H-pyrrolo[2,3-c]pyridine (259)

To a solution of 2-chloro-3-nitropyridine (5 g, 31.5 mmol)) in THF (200mL) at −78° C., was added vinylmagnesium bromide (100 mL, 1.0M in THF)The reaction mixture was stirred at −20° C. for 8 hours, quenched withNH₄Cl solution (20%, 150 mL), extracted with EtOAc, dried over anhydrousNa₂SO₄ and concentrated. The residue was purified by flashchromatography, eluent EtOAc/hexane (1:5), to afford the title compound259 (1.23 g, 26% yield) as a white solid [Z. Zhang, et al. J. Org.Chem., 2002, 67, 2345-2347]. MS (m/z): 153.1 (M+H) (found).

Step 2. 7-(2-Fluoro-4-nitrophenoxy)-1H-pyrrolo[2,3-c]pyridine (260)

A mixture of 259 (420 mg, 2.76 mmol), 2-fluoro-4-nitrophenol (651 mg,4.14 mmol) and K₂CO₃(1.14 g, 8.28 mmol) in Ph₂O (15 mL) was heated at200° C. for 6 hours, cooled to room temperature and partitioned betweenEtOAc and water. Organic phase was collected, dried and concentrated.The residue was purified by flash column chromatography with gradientelution from hexane to hexane/EtOAc (3:1), to afford the title compound260 (333 mg, 44% yield) as a yellowish solid. MS (m/z): 274. 1 (M+H)(found).

Step 3. 4-(1H-Pyrrolo[2,3-c]pyridin-7-yloxy)-3-fluorobenzenamine (261)

To a solution of 260 (100 mg, 0.36 mmol) in AcOH (4 mL) at 90° C., wasadded iron powder (102 mg, 2.1 mmol). The reaction mixture wasvigorously stirred for 10 min, cooled, filtered through a Celite pad andconcentrated. The residue was purified by flash column chromatography,eluent EtOAc/hexane (1:1), to afford title compound 261 (87 mg, 99%yield) as an off-white solid. MS (m/z): 244.1 (M+H) (found).

Step 4.N-(4-(1H-Pyrrolo[2,3-c]pyridin-7-yloxy)-3-fluorophenylcarbamothioyl)-2-phenylacetamide(262a)

A mixture of 261 (44 mg, 0.18 mmol) and 2-phenylacetyl isothiocyanate(36 □L, 0.19 mmol) in THF (2 mL) was stirred at room temperature for 2hours, and concentrated. The residue was purified by flash columnchromatography, eluent EtOAc/hexane (1:1), to afford the title compound262a (30 mg, 40%) as an off-white solid. ¹H NMR (DMSO-d₆) δ (ppm): 12.41(s, 1H), 12.07 (s, 1H), 11.77 (s, 1H), 7.84(dd, 1H, J₁=10.95 Hz, J₂=2.0Hz), 7.58(t, 1H, J₁=J₂=2.7 Hz), 7.51(d, 1H, J=5.7 Hz), 7.43-7.39 (m,2H), 7.37-7.33(m, 4H), 7.31-7.26 (m, 2H), 6.55(dd, 1H, J₁=1.76 Hz,J₂=2.9 Hz), 3.84 (s, 2H), MS (m/z): 421.1 (M+H) (found).

Example 219N-(3-Fluoro-4-(1-methyl-1H-pyrrolo[2,3-c]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(262b) Step 1. 7-Chloro-1-methyl-1H-pyrrolo[2,3-c]pyridine (263)

To a solution of 259 (250 mg, 1.64 mmol) in DMF (16 mL) at 0° C. wasadded NaH (197 mg, 4.92 mmol, 60% in mineral oil), and the mixture wasstirred for 30 min, followed by addition of MeI (112 □L, 1.80 mmol). Thereaction mixture was stirred at room temperature for 2 h before aceticacid (1 mL) was added. Solvents were removed under reduced pressure, theresidue was partitioned between water and EtOAc. Organic phase wascollected, dried over anhydrous Na₂SO₄ and concentrated. The residue waspurified by flash column chromatography, eluent EtOAc/hexane (1:1), toafford the title compound 263 (200 mg, 92% yield) as an off-white solid.MS (m/z): 167.1 (M+H) (found).

Step 2. 7-(2-Fluoro-4-nitrophenoxy)-1-methyl-1H-pyrrolo[2,3-c]pyridine(264)

Starting from the compound 263 and following the procedure describedabove for the synthesis of nitro compound 260 (scheme 59, step 2,example 218), title compound 264 was obtained in 91% yield as a yellowsolid. MS (m/z): 288.1 (M+H) (found).

Step 3.-Fluoro-4-(1-methyl-1H-pyrrolo[2,3-c]pyridin-7-yloxy)benzenamine(265)

Starting from the compound 264 and following the procedure describedabove for the synthesis of amine 261 (scheme 59, step 3, example 218),title compound 265 was obtained in 89% yield as an off-white solid. MS(m/z): 258.1 (M+H) (found).

Step 4.N-(3-Fluoro-4-(1-methyl-1H-pyrrolo[2,3-c]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(262b)

Starting from the compound 265 and following the procedure describedabove for the synthesis of compound 262a (scheme 59, step 4, example218), title compound 262b was obtained in 87% yield as an off-whitesolid. ¹H NMR (DMSO-d₆) δ (ppm): 12.40 (s, 1H), 11.78 (s, 1H), 7.83(dd,1H, J₁=10.95 Hz, J₂=1.9 Hz), 7.56(d, 1H, 2.7 Hz), 7.49(d, 1H, J=5.5 Hz),7.43-7.39 (m, 2H), 7.37-7.33 (m, 4H), 7.31-7.26 (m, 2H), 6.52(d, 1H,J₂=2.9 Hz), 4.11 (s, 3H), 3.84 (s, 2H), MS (m/z): 435.1 (M+H) (found).

Example 220

N-(4-(1-Benzyl-1H-pyrrolo[2,3-c]pyridin-7-yloxy)-3-fluorophenylcarbamothioyl)-2-phenylacetamide(262c)

Starting from the compound 259 and following the procedures describedabove for the synthesis of compound 262b (scheme 60, step 4, example219) but using benzyl bromide in step 1 instead of methyl iodide, titlecompound 262c was obtained. ¹H NMR (DMSO-d₆) δ (ppm): 12.36 (s, 1H),11.76 (s, 1H), 7.78 (m, 1H), 7.58(t, 1H, J₁=J₂=2.7 Hz), 7.50(d, 1H,J=5.7 Hz), 7.34 (m, 5H), 7.30-7.221 (m, 5H), 7.15(dd, 1H, J₁=8.1 Hz,J₂=0.4 Hz), 7.10(t, 1H), 6.60(d, 1H, J=2.9 Hz), 5.68 (s, 2H), 3.82 (s,2H). MS (m/z): 511.2 (M+H) (found).

Example 221N-(4-(1H-Pyrrolo[3,2-b]pyridin-7-yloxy)-3-fluorophenylcarbamothioyl)-2-phenylacetamide (269a) Step 1. 7-Chloro-1H-pyrrolo[3,2-b]pyridine (266)

To a solution of 2-chloro-3-nitropyridine (2.0 g, 12.6 mmol) [C.Almansa, et al. J. Med. Chem. 2001, 44, 350-361] in THF (80 mL) at −78°C., was added vinylmagnesium bromide (80 mL, 1.0M in THF), and thereaction mixture was stirred at −20° C. for 8 hours, quenched with NH₄Clsolution (20%, 100 mL), extracted with EtOAc, dried over anhydrousNa₂SO₄ and concentrated. The residue was purified by flash columnchromatography, eluent EtOAc/Hexane (1:1), to afford the title compound266 (240 mg, 11%) as yellow crystals. MS (m/z): 153.1 (M+H) (found).

Step 2. 7-(2-Fluoro-4-nitrophenoxy)-1H-pyrrolo [3,2-b]pyridine (267)

A mixture of 266 (180 mg, 1.18 mmol), 2-fluoro-4-nitrophenol (558 mg,3.55 mmol) and K₂CO₃(981 mg, 7.10 mmol) in Ph₂O (4 mL) was heated at170° C. for 8 hours, cooled to room temperature and partitioned betweenEtOAc and water. Organic phase was collected, dried over anhydrousNa₂SO₄ and concentrated. The residue was purified by flash columnchromatography with gradient elution of hexane, to hexane/EtOAc (1:1),to afford the title compound 267 (84 mg, 26% yield) as a yellowishsolid. MS (m/z): 274. 1 (M+H) (found).

Step 3. 4-(1H-Pyrrolo[3,2-b]pyridin-7-yloxy)-3-fluorobenzenamine (268)

To a solution of 267 (35 mg, 0.13 mmol) in AcOH (1 mL) at 90° C., wasadded iron powder (36 mg, 0.65 mmol). The reaction mixture was stirredvigorously for 10 min, cooled, filtered through a Celite pad andconcentrated. The residue was partitioned between DCM and NaHCO₃saturated solution. Phases were separated; the aqueous phase wasneutralized with AcOH and extracted with DCM. Primary organic phase andthe extract were combined and concentrated to give the title compound268 (31 mg, 99%) as an off-white solid. MS (m/z): 244. 1 (M+H) (found).

Step 4.N-(4-(1H-Pyrrolo[3,2-b]pyridin-7-yloxy)-3-fluorophenylcarbamothioyl)-2-phenylacetamide (269a)

A mixture of 268 (20 mg, 0.08 mmol) and 2-phenylacetyl isothiocyanate(16 □L, 0.08 mmol) in THF (1 mL) was stirred at room temperature for 2hours and concentrated. The residue was purified by flash columnchromatography (eluent EtOAc) followed by preparative HPLC (columnAqusil C18, gradient elution with 60-95% MeOH in water, 45 min) toafford the title compound 269a (13 mg, 40% yield) as an off-white solid.¹H NMR (CD₃OD) δ (ppm): 8.41 (s, 1H), 8.16 (d, 1H, J=5.6 Hz), 8.02 (dd,1H, J₁=2.3Hz, J₂=12.2 Hz), 7.62 (d, 1H, J=3.3 Hz), 7.44 (m, 1H),7.37-7.33 (m, 4H) 7.31-7.26 (m, 1H), 6.65(d, 1H, J=3.1 Hz), 6.52(d, 1H,J=5.7 Hz), 3.76 (s, 2H), MS (m/z): 421.1 (M+H) (found).

Example 222N-(4-(1H-Pyrrolo[3,2-b]pyridin-7-yloxy)-3-fluorophenylcarbamothioyl)-2-(2,6-dichlorophenyl)acetamidedihydrochloride (269b)

Starting from the compound 268 and following the procedure describedabove for the synthesis of compound 269a (example 221) but replacing2-phenylacethyl isothiocyanate with 2-(2,6-dichlorophenyl)acetylisothiocyanate, a white solid was obtained. This material was dissolvedin MeOH and treated with HCl (1 mL, 1.0M in ether). Solvents wereremoved under the reduced pressure and the residue was lyophilized, toafford the title compound 269b (48% yield) as a yellowish solid. ¹H NMR(DMSO-d₆) δ (ppm): 13.29 (s, 1H), 12.32 (s, 1H), 12.05(s, 1H), 8.52(d,1H), 8.14 (m, 2H), 7.64 (m, 2H), 7.51(d, 1H), 7.37(dd, 1H), 6.86 (m,1H), 6.81(dd, 1H), 4.22 (s, 2H), MS (m/z): 489.1 (M+H) (found).

Example 223N-(4-(6-Bromothieno[3,2-b]pyridin-7-yloxy)-3-fluorophenylcarbamothioyl)-2-phenylacetamide(274) Step 1. 6-Bromothieno[3,2-b]pyridin-7-ol (270)

To a solution of thieno[3,2-b]pyridin-7-ol (1, 2.55 g, 16.87 mmol) inacetic acid (50 mL) was added bromine (1.7 mL, 32.72 mmol). The mixturewas heated at 110° C. for 1 h, cooled and the resultant precipitate wasseparated by filtration, to afford the title compound 270 (4.47 g,crude) as a dark brown powder, which was used in next step withoutfurther purification. M/S (m/z): 231.9 (M+H) (found).

Step 2. 6-Bromo-7-chlorothieno[3,2-b]pyridine (271)

DMF (0.72 mL) was added slowly to a solution of (COCl)₂ in DCE at 0° C.and the mixture was stirred for 30 min, followed by addition of 270(crude from above). The combined mixture was stirred for 10 min at thesame conditions and was heated to reflux for 3 h. After cooling themixture was concentrated and partitioned between DCM and water. Organicphase was collected and dried over anhydrous Na₂SO₄, filtered andconcentrated. The residue was purified by flash column chromatography(eluent EtOAc), to afford the title compound 271 (0.66 g, 70% yieldbased on compound 1) as a yellowish solid. MS (m/z): 249.0 (M+H)(found).

Step 3. 6-Bromo-7-(2-fluoro-4-nitrophenoxy)thieno[3,2-b]pyridine (272)

Starting from the compound 271 and following the procedure describedabove for the synthesis of compound 260 (scheme 59, example 218, step2), title compound 272 was obtained in 61% yield as an off-white solid.MS (m/z): 368.9 (M+H).

Step 4. 4-(6-Bromothieno[3,2-b]pyridin-7-yloxy)-3-fluorobenzenamine(273)

Starting from the compound 272 and following the procedure describedabove for the synthesis of compound 261 (scheme 59, example 218, step3), title compound 273 was obtained in 92% yield as a light brown solid.MS (m/z): 340.0 (M+H).

Step 5.N-(4-(6-Bromothieno[3,2-b]pyridin-7-yloxy)-3-fluorophenylcarbamothioyl)-2-phenylacetamide(274)

Starting from the compound 273 and following the procedure describedabove for the synthesis of compound 262a (scheme 59, example 218, step4), title compound 274 was obtained in 99% yield as a white solid. ¹HNMR (DMSO-d₆) δ (ppm): 12.44 (s, 1H), 11.79(s, 1H), 8.82 (s, 1H),8.03(d, 1H), 7.99(dd, 1H), 7.54(d, 1H), 7.41(dd, 1H), 7.32-7.24 (m, 6H),3.80 (s, 2H). MS (m/z): 517.0 (M+H) (found).

Example 2244-(2-Fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)-N,N,7-trimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (279) Step 1. Lithium4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylate (275)

To a solution of 2,2,6,6-tetramethylpiperidine (92 μL, 0.54 mmol) in THF(4 mL) at −10° C., n-BuLi (338 μL, 1.6M in hexane, 0.54 mmol) was addeddrop wise and the reaction mixture was stirred at −10° C. for 10 min.Compound 33 (60 mg, 0.36 mmol) [G. B. Evans et al. J. Org. Chem. 2001,66, 17, 5723-5730 and shown in the scheme 6] was added drop wisemaintaining the temperature below −70° C. over a period of 15 min. DriedCO₂-gas was bubbled through the reaction mixture and stirred at roomtemperature overnight. The precipitate thus formed was collected byfiltration and dried to afford the title compound 275 (78 mg, 100%yield) as a yellow solid. MS (m/z): 209.9 (RCOOH, M−H) (found).

Step 2.4-Chloro-N,N,7-trimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (276)

A reaction mixture containing carboxylate 275 (78 mg, 0.36 mmo), oxalylchloride (63 uL, 0.72 mmol), and a drop of DMF in DCM was stirred for 2h. Solvents were removed under reduced pressure and the residue wasre-dissolved in DCM (4 mL). To this solution Me₂NH (360 μL, 0.72 mmol,2M in THF) in THF was added and the mixture was stirred at roomtemperature for 4 h. The solvent was removed under reduced pressure andthe residue was purified by flash column chromatography (eluent EtOAc)to afford the title compound 276 (50 mg, 58% yield) as a yellowishsolid. MS (m/z): 239.1 (M+H) (found).

Step 3.4-(2-Fluoro-4-nitrophenoxy)-N,N,7-trimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide(277)

Starting from the compound 276 and following the procedure describedabove for the synthesis of compound 260 (scheme 59, example 218, step 2)title compound 277 was obtained in 77% yield as an off-white solid. MS(m/z): 360.1 (M+H) (found).

Step 4.4-(4-Amino-2-fluorophenoxy)-N,N,7-trimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide(278)

Starting from the compound 277 and following the procedure describedabove for the synthesis of compound 261 (scheme 59, example 218, step 3)title compound 278 was obtained in 72% yield as an off-white solid. MS(m/z): 330.1 (M+H) (found).

Step 5.4-(2-Fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)-N,N,7-trimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (279)

Starting from the compound 278 and following the procedure describedabove for the synthesis of compound 262a (scheme 59, example 218, step4) title compound 279 was obtained in 98% yield as an off-white solid.1H NMR (DMSO-d6) δ (ppm): 12.45 (s, 1H), 11.81 (s, 1H), 8.43 (s, 1H),7.89 (m, 1H), 7.46 (m, 2H), 7.34 (m, 4H), 7.28(m, 1H), 6.93 (m, 1H),4.03 (s, 3H), 3.82 (s, 2H), 3.81 (s, 3H), 3.14 (s, 3H), 3.06 (s, 3H). MS(m/z): 507.1 (M+H) (found).

Example 225N-(3-Fluoro-4-(6-(methylthio)thieno[3,2-d]pyrimidin-4-yloxy)phenylcarbamothioyl)-2-phenylacetamide(283) Step 1. 4-chloro-6-(methylthio)thieno[3,2-d]pyrimidine (280)

To a solution of 20 (shown in the scheme 4) (200 mg, 1.18 mmol) in THF(11 mL) was added n-BuLi (566 μL, 1.42 mmol, 2.5M in THF) very slowly at−78° C. and the mixture was stirred for 15 min at the same conditions. Asolutions of dimethyl disulfide (160 uL, 1.77 mmol) and MeI (110 μL,1.77 mmol) in THF (1 mL) was added drop wise. The reaction mixture wasstirred for 2 h at −78° C., quenched with saturated aqueous NH₄Clsolution, and extracted with DCM. The extract was dried over anhydrousNa₂SO₄ and concentrated to afford the title compound 280 (210 mg, 82%yield) as a yellowish solid. MS (m/z): 217.0 (M+H) (found).

Step 2.4-(2-Fluoro-4-nitrophenoxy)-6-(methylthio)thieno[3,2-d]pyrimidine (281)

A mixture of 280 (210 mg, 0.97 mmol), 2-fluoro-4-nitrophenol (278 mg,1.77 mmol) and K₂CO₃ (560 mg, 3.54 mmol) in Ph₂O (10 mL) was heated at130° C. 60 hours, cooled to room temperature and partitioned betweenEtOAc and water. Organic phase was collected, dried over anhydrousNa₂SO₄, filtered, concentrated and purified by flash columnchromatography with a gradient elution (hexane to hexane/EtOAc, 1:1) toafford the title compound 281 (288 mg, 88% yield) as a yellowish solid.MS (m/z): 338.1 (M+H) (found).

Step 3.3-Fluoro-4-(6-(methylthio)thieno[3,2-d]pyrimidin-4-yloxy)benzenamine(282)

To a solution of 281 (288 mg, 0.94 mmol) in AcOH (25 mL) at 90° C., wasadded iron powder (238 mg, 4.25 mmol), and the reaction mixture wasstirred vigorously at 90° C. for 10 min, cooled, filtered through aCelite pad and concentrated. The residue was purified by flash columnchromatography (eluent EtOAc) to afford the title compound 282 (248 mg,95%) as an off-white solid. MS (m/z): 308.1 (M+H) (found).

Step 4.N-(3-Fluoro-4-(6-(methylthio)thieno[3,2-d]pyrimidin-4-yloxy)phenylcarbamothioyl)-2-phenylacetamide(283)

A mixture of 282 (248 mg, 0.80 mmol) and 2-phenylacetyl isothiocyanate(214 mg, 1.20 mmol) in THF (8 mL) was stirred for 2 hours, andconcentrated. The residue was purified by flash column chromatography,eluent EtOAc/hexane (3:7), to afford title compound 283 (200 mg, 52%yield) as an off-white solid. ¹H NMR (DMSO-d₆) δ (ppm): 12.42 (s, 1H),11.80(s, 1H), 8.63 (s, 1H), 7.85(d, 1H), 7.54-7.44 (m, 3H), 7.35 (m,4H), 7.30 (m, 1H), 3.81 (s, 2H), MS (m/z): 485.1 (M+H) (found).

Example 226N-(3-Fluoro-4-(6-(methylsulfinyl)thieno[3,2-d]pyrimidin-4-yloxy)phenylcarbamothioyl)-2-phenylacetamide (286) Step 1.4-(2-Fluoro-4-nitrophenoxy)-6-(methylsulfinyl)thieno[3,2-d]pyrimidine(284)

A mixture of 281 (1.1 g, 3.2 mmol) and m-CPBA (77%, 890 mg, 12.8 mmol)in DCM at 0° C. was stirred for 2 hours, diluted with DCM, washed withice water, NaHCO₃ solution and water again; dried and concentrated togive the title compound 284 (1.15 g, quantitative) as a yellowish solid.MS (m/z): 354.0 (M+H) (found).

Step 2.4-(2-Fluoro-4-nitrophenoxy)-6-(methylsulfinyl)thieno[3,2-d]pyrimidine(285)

Starting from the compound 284 and following the procedure describedabove for the synthesis of compound 282 (scheme 64, step 3, example225), title compound 285 was obtained in 34% yield as an off-whitesolid. MS (m/z): 324.0 (M+H) (found).

Step 3.N-(3-Fluoro-4-(6-(methylsulfinyl)thieno[3,2-d]pyrimidin-4-yloxy)phenylcarbamothioyl)-2-phenylacetamide (286)

Starting from the compound 285 and following the procedure describedabove for the synthesis of compound 283 (scheme 64, step 4, example225), title compound 286 was obtained in 36% yield as an off-whitesolid. ¹H NMR (DMSO-d₆) δ (ppm): 12.45 (s, 1H), 11.83 (s, 1H), 8.80 (s,1H), 8.13 (s, 1H), 7.93(dd, 1H, J₁=2.3 Hz, J₂=10.9 Hz), 7.55 (t, 1H,J=8.6 Hz), 7.48 (m, 1H), 7.34-7.31 (m, 4H), 7.28-7.25 (m, 1H), 3.81 (s,2H), 3.08 (s, 3H). MS (m/z): 501.0 (M+H) (found).

Example 227 Methyl7-(2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)thieno[3,2-b]pyridine-2-carboxylatehydrochloride (288) Step 1. Methyl7-(4-amino-2-fluorophenoxy)thieno[3,2-b]pyridine-2-carboxylate (287)

Starting from the nitro compound 38 (shown in the scheme 7) andfollowing the procedure described above for the synthesis of compound261 (scheme 59, step 3, example 218), title compound 287 was obtained in86% yield as an off-white solid. MS (m/z): 319.0 (M+H) (found).

Step 2. Methyl7-(2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)thieno[3,2-b]pyridine-2-carboxylatehydrochloride (288)

Starting from the amine 287, following the procedure described above forthe synthesis of compound 269b (scheme 561, example 222) and replacing2-(2,6-dichlorophenyl)acetyl isothiocyanate with 2-phenylacetylisothiocyanate, title compound 288 was obtained in 72% yield as ayellowish solid. ¹H NMR (d-DMSO) δ (ppm): 12.51 (s, 1H), 11.84 (s, 1H),8.64(dd, 1H, J₁=5.1 Hz, J₂=0.4 Hz), 8.24 (s, 1H, J=0.4Hz), 8.02(dd, 1H,J₁=1.8 Hz, J₂=13.4 Hz), 7.56-7.54 (m, 2H), 7.36-7.31 (m, 1H), 7.28-7.25(m, 1H), 6.81 (d, 1H, J=5.5 Hz), 3.91 (s, 3H), 3.81 (s, 2H). MS (m/z):496.3 (M+H) (found).

Example 2287-(2-Fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)-N-(pyrrolidin-3-yl)thieno[3,2-b]pyridine-2-carboxamide(291) Step 1. tert-Butyl3-(7-(2-fluoro-4-nitrophenoxy)thieno[3,2-b]pyridine-2-carboxamido)pyrrolidine-1-carboxylate(289)

A solution of 40 (shown in the scheme 7, 600 mg, 1.54 mmol), tert-butyl3-aminopyrrolidine-1-carboxylate (369 mg, 2.0 mmol) in DCM (15 mL) wasstirred overnight at room temperature. The solvent was removed underreduced pressure and the residue was purified by flash columnchromatography, eluents EtOAc and EtOAc/MeOH (10:1), to afford the titlecompound 289 (160 mg, 20%) as an off-white solid. MS (m/z): 503.3 (M+H)(found).

Step 2. tert-Butyl3-(7-(4-amino-2-fluorophenoxy)thieno[3,2-b]pyridine-2-carboxamido)pyrrolidine-1-carboxylate(290)

A mixture of 289 (90 mg, 0.18 mmol) and Pd(OH)₂ in MeOH (2 mL) washydrogenated at 1 atm for 1 h. The catalyst was filtered off and thefiltrate was concentrated to afford the title compound 290 (60 mg, 70%yield) as a yellowish solid. MS (m/z): 473.2 (M+H) (found).

Step 3.7-(2-Fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)-N-(pyrrolidin-3-yl)thieno[3,2-b]pyridine-2-carboxamide(291)

A solution of 290 (40 mg, 0.084 mmol) and 2-phenylacetyl isothiocyanate(22 mg, 0. 126 mmol) in THF (2 mL) was stirred for 30 min. The solventwas removed under reduced pressure and the residue was purified by flashcolumn chromatography (eluent EtOAc), to afford a solid material, whichwas dissolved in a mixture of TFA/DCM (0.5 mL/0.5 mL) and stirred atroom temperature for 2 h. Solvents were removed under reduced pressureand the residue was purified by preparative HPLC (Aqusil C18, gradienteluent, 60-95% MeOH in water, 45 min) to afford the title compound 291(8 mg, 80% yield) as an off-white solid. ¹H NMR (d-DMSO) δ (ppm):9.27(d, 1H), 8.57(d, 1H), 8.37 (s, 1H), 8.30 (s, 1H), 8.01(d, 1H), 7.53(m, 2H), 7.33-7.31 (m, 4H), 7.29-7.25 (m, 1H), 6.74(d, 1H), 4.46 (m,1H), 3.82 (s, 2H), 3.11-3.03 (m, 2H), 2.18-2.09 (m, 2H), 1.93-1.89 (m,2H). MS (m/z): 550.2 (M+H) (found).

Example 229N-(2-Aminoethyl)-7-(2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)thieno[3,2-b]pyridine-2-carboxamide(294) Step 1. tert-Butyl2-(7-(2-fluoro-4-nitrophenoxy)thieno[3,2-b]pyridine-2-carboxamido)ethylcarbamate(292)

A solution of 40 (shown in the scheme 7, 100 mg, 0.26 mmol),N-Boc-N-methylethylenediamine hydrochloride (50 mg, 0.26 mmol) and Et₃N(36 μL, 0.52 mmol) in DCM (2 mL) was stirred for 4 h at room temperatureand diluted with EtOAc (10 mL). The combined mixture was washed withbrine and phases were separated. The aqueous phase was extracted withEtOAc, and the extract was combined with the organic phase, dried overanhydrous Na₂SO₄ and concentrated to afford title compound 292 (119 mg,96%, crude) as yellowish solid. MS (m/z): 477.1 (M+H) (found).

Step 2. tert-Butyl2-(7-(4-amino-2-fluorophenoxy)thieno[3,2-b]pyridine-2-carboxamido)ethylcarbamate(293)

To a solution of 292 (80 mg, 0.17 mmol) in MeOH/THF (1.7 mL/1.7 mL) at0° C., was added NiCl₂×6H₂O (85 mg, 0.35 mmol), followed by addition ofNaBH₄ (26 mg, 0.68 mmol), portion wise. The reaction mixture was stirredfor 15 min, treated with 2N aqueous HCl (2 mL), filtered; the filtratewas neutralized with aqueous NH₄OH to pH 7 and partitioned between EtOAcand water. Organic phase was collected, dried over anhydrous Na₂SO₄ andconcentrated. The residue (75 mg, quantitative yield, crude) was useddirectly in next step without further purification. MS (m/z): 447. 1(M+H) (found).

Step 3.N-(2-Aminoethyl)-7-(2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)thieno[3,2-b]pyridine-2-carboxamide(294)

Following the procedure described above for the synthesis of compound291 (example 228), title compound was obtained in 3% yield as anoff-white solid. ¹H NMR (d-DMSO) δ (ppm): 9.00(d, 1H), 8.50 (m, 1H),8.30 (m, 1H), 8.20(d, 1H), 7.92(d, 1H, 7.44 (m, 2H), 7.26-7.25 (m, 3H),7.21-7.18 (m, 1H), 6.66(d, 1H), 3.75 (s, 2H), 3.30-3.20 (m, 6H), MS(m/z): 524.3 (M+H).

Example 230N-(3-Fluoro-4-(2-(3-hydroxyazetidine-1-carbonyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-(2-methoxyphenyl)acetamide(300) Step 1. tert-Butyl3-(tert-butyldimethylsilyloxy)azetidine-1-carboxylate (295)

A solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (1 g, 5.77mmol), TBSCl (6.35 mmol, 956 mg) in DCM (11.5 mL), was stirred for 72hrs at room temperature. The solvent was removed under reduced pressure,EtOAc was added to the residue, and the solid material was removed byfiltration. The filtrate was concentrated under reduced pressure and theresidue was purified by flash chromatography with gradient elution withEtOAc/hexane (9:1) to EtOAc/hexane (1:1), to afford title compound 295(1.25 g, 75% yield) as a syrup. MS (m/z): 310.1 (M+23).

Step 2: 3-(tert-Butyldimethylsilyloxy)azetidine (296)

A mixture of 295 (200 mg, 0.696 mol), DCM (1 mL) and TFA (1 mL) wasstirred for 1 h at room temperature, concentrated under reducedpressure; NaOH (1M, 15 mL) was added to the residue and the suspensionwas extracted with DCM, the extract was dried (anhydrous Na₂SO₄) andconcentrated, to afford title compound 296 (90.4 mg, 69% yield) as asyrup. MS (m/z): 188.1 (M+1).

Step 3:(3-(tert-Butyldimethylsilyloxy)azetidin-1-yl)(7-chlorothieno[3,2-b]pyridin-2-yl)methanone(297)

Starting from the acyl chloride 4 (scheme 1), replacing dimethyl aminewith the amine 296 and following the procedure described for thesynthesis of amide 5 (scheme 1 as well), title compound 297 was obtainedin 64% yield as a syrup. MS (m/z): 383.0 (M+1).

Step 4:(7-(2-Fluoro-4-nitrophenoxy)thieno[3,2-b]pyridin-2-yl)(3-hydroxyazetidin-1-yl)methanone(298)

Starting from the amide 297 and following the procedure described abovefor the synthesis of compound 230 (scheme 50, example 203), titlecompound 298 was obtained in 39% yield as a syrup. MS (m/z): 389.05(M+1).

Step 5:(7-(4-Amino-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)(3-hydroxyazetidin-1-yl)methanone(299)

Starting from the nitro compound 298 and following the proceduredescribed above for the synthesis of the amine 231 (scheme 50, example203), title compound 299 was obtained in 83% yield. MS (m/z): 359.07(M+1).

Step 6:N-(3-Fluoro-4-(2-(3-hydroxyazetidine-1-carbonyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-(2-methoxyphenyl)acetamide(300)

Starting from the amine 299, following the procedure described above forthe synthesis of compound 232a (scheme 50, example 203) but replacing2-phenylacetyl isothiocyanate with (2-methoxy-phenyl)-acetylisothiocyanate and title compound 300 was obtained in 39% yield as acreamy solid. ¹HNMR: (CD₃OD) δ (ppm): 12.58 (s, 1H), 11.77 (s, 1H), 8.62(m, 1H), 8.09 (d, J=12.3 Hz, 1H), 7.95 (s, 1H), 7.56 (m, 2H), 7.26 (m,2H), 7.00 (m, 1H), 6.92 (m, 1H), 6.77 (m, 1H), 6.50 (d, J=5.9 Hz, 1H),4.81 (m, 1H), 4.59 (m, 1H), 4.35 (m, 2H), 3.87-3.78 (m, 6H). MS (m/z):567.0 (M+1).

Example 231N-(4-(2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-ylamino)phenylcarbamothioyl)-2-phenylacetamide (302) Step 1.N4-(2-(1-Methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yl)benzene-1,4-diamine(301)

A mixture of 214 (500 mg, 2.0 mmol, scheme 46) and benzene-1,4-diamine(500 mg, 4.62 mmol) in iso-PrOH (15 mL) was refluxed overnight, cooledto room temperature and filtered. The solid was collected, washed withiso-PrOH/H₂O mixture, to afford the title compound 301 (300 mg, 44%yield) as a yellowish solid. MS (m/z): 322.1 (M+H) (found).

Step 2.N-(4-(2-(1-Methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-ylamino)phenylcarbamothioyl)-2-phenylacetamide (302)

Starting from the compound 301, following the procedures described abovefor the synthesis of compound 269b (scheme 61, example 222) butreplacing 2-(2,6-dichlorophenyl)acetyl isothiocyanate with2-phenylacethyl isothiocyanate, title compound 302 was obtained in 12%yield, as a yellow solid. ¹H NMR (d-DMSO) δ (ppm): 12.47 (s, 1H), 11.76(s, 1H), 10.83 (s, 1H), 8.41(d, 1H, J=6.9Hz), 7.84 (s, 1H), 7.80 (s,1H), 7.78 (s, 1H), 7.55(s, 1H), 7.46 (s, 1H), 7.43 (s, 1H), 7.32 (m,4H), 7.28-7.20 (m, 1H), 7.20 (s, 1H), 6.94(d, 1H, J=6.8 Hz), 3.98 (s,3H), 3.81 (s, 2H). MS (m/z): 499.1 (M+H) (found).

Example 232N-(3-Fluoro-4-(2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl carbamothioyl)-2-(2-fluorophenyl)acetamide di-hydrochloride(303a)

A mixture of aniline 219 (100 mg, 0.29 mmol, scheme 47) and2-(2-fluorophenyl)acetyl isothiocyanate (115 mg, 0.58 mmol) in THF (3mL) was stirred for 1 hour, loaded directly onto a column containingsilica gel and eluted sequentially with EtOAc and EtOAc/MeOH (100:1), toproduce a white solid. This material was suspended in MeOH (5 mL) andHCl (1.0M in ether, 1 mL) was added to form a clear solution that wasevaporated to dryness. The residue was washed with ether, suspended inH₂O, and lyophilized to afford the title compound (80 mg, 45% yield) asa yellowish solid. ¹H-NMR (DMSO-d₆) δ (ppm): 12.42(s, 1H), 11.88 (s,1H), 8.65(d. 1H, J=5.5 Hz), 8.20 (s, 1H), 8.05(d, 1H, J=1.7Hz), 7.74 (s,1H), 7.58-7.55 (m, 3H) 7.39-7.32 (m, 2H), 7.21-7.16 (m, 2H), 6.82(d, 1H,J=5.5 Hz), 4.02 (s, 3H), 3.93(s, 2H), MS (m/z): 536.2 (M+H) (found).

Example 233N-(3-Fluoro-4-(2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-(2-methoxyphenyl)acetamidedi-hydrochloride (303b)

Starting from the compound 219, following the procedure described abovefor the synthesis of 303a (example 232) but replacing2-(2-fluorophenyl)acetyl isothiocyanate with 2-(2-methoxyphenyl)acetylisothiocyanate, title compound 303b was obtained in 44% as an off-whitesolid. ¹H NMR (d-DMSO) δ (ppm): 12.55 (s, 1H), 11.73 (s, 1H), 8.62 (m,1H), 8.09(m, 1H), 7.65 (s, 1H), 7.57 (m, 1H), 7.43 (s, 1H), 7.27-7.20(m, 1H), 6.98(d, 1H, J=8.2 Hz), 6.90(dt, 1H, J₁=10 Hz, J₂=7.4 Hz), 6.79(m, 1H), 4.02 (s, 3H), 3.81 (s, 2H), 3.77 (s, 3H). MS (m/z): 548.3 (M+H)(found).

Example 2342-(2-Fluorophenyl)-N-(4-(2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)acetamidedihydrochloride (304)

Starting from the compound 214 (scheme 46) and following the proceduresdescribed above for the synthesis of compound 228 (example 202) and 303a(example 232), title compound 234 was obtained in 31% yield as anoff-white solid. ¹H NMR (d-DMSO) δ (ppm): 12.34 (s, 1H), 11.81 (s, 1H),8.68 (m, 1H), 8.24 (s, 1H), 7.79 (m, 3H), 7.62 (s, 1H), 7.40-7.13 (m,6H), 6.86(d, 1H), 4.02 (s, 3H), 3.93 (s, 2H). MS (m/z): 518.1 (M+H)(found).

SCHEME 71

194 (scheme 40) 219 (scheme 47) 177 (scheme 35)

305a: Example 235 305b: Example 236 305c: Example 237 R Compound No

194 and 305a

219 and 305b

177 and 305c

Examples 235N-(3-Fluoro-4-(2-(pyrrolidine-1-carbonyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamoyl)-2-phenylacetamide hydrochloride (305a)

A mixture of 194 (93 mg, 0.26 mmol, scheme 40) and 2-phenylacetylisocyanate (83 mg, 0.62 mmoL) [J. Hill et al. JACS, 62; 1940; 1595] wasstirred for 1 h at room temperature, loaded directly onto a flashchromatography column and eluted with EtOAc. A white solid was obtained,which was suspended in MeOH and treated with HCl (1 mL, 1.0M in Et₂O) toform a clear solution. The solution was concentrated to form aprecipitate which was collected by filtration, to afford the titlecompound 305a (48 mg, 33% yield) as a white solid. ¹H NMR (d-DMSO) δ(ppm): 11.05 (s, 1H), 10.62 (s, 1H), 8.57(d, 1H), 8.02 (s, 1H), 7.81(d,1H), 7.48-7.43 (m, 2H), 7.33-7.25 (m, 5H), 6.74(d, 1H), 3.85(t, 2H),3.78 (s, 2H), 3.51(t, 2H), 1.98-1.86(m, 2H). MS (m/z): 519.2 (M+H)(found).

Example 236N-(3-Fluoro-4-(2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamoyl)-2-phenylacetamide dihydrochloride (305b)

Starting from the compound 219 (scheme 47) and following the proceduredescribed above for the synthesis of compound 305a, title compound 305bwas obtained in 15% yield as a white solid. ¹H NMR (d-DMSO) δ (ppm):11.07 (s, 1H), 10.66 (s, 1H), 8.67(d, 1H, J=5.5 Hz), 8.27 (s, 1H),7.85-7.80 (m, 2H), 7.65 (s, 1H), 7.51(t, 1H, J=8.6Hz), 7.46(d, 1H),7.34-7.28(m, 5H), 6.85(d, 1H, J=5.3 Hz), 4.03 (s, 3H), 3.74 (s, 2H). MS(m/z): 502.2 (M+H) (found).

Example 237N-(3-Fluoro-4-(2-(1-methyl-1H-imidazol-4-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamoyl)-2-phenylacetamide dihydrochloride (305c)

Starting from the compound 177 (scheme 35) and following the proceduredescribed above for the synthesis of compound 305a, title compound 305cwas obtained in 54% yield as a white solid. ¹H NMR (d-DMSO) δ (ppm):11.08 (s, 1H), 10.67 (s, 1H), 8.66 (d, 1H, J=6.2 Hz), 8.26 (s, 1H), 8.21(s, 1H), 7.93 (s, 1H), 7.85(dd, 1H, J₁=12.9 Hz, J₂=2.5 Hz), 7.53(t, 1H,J=8.8 Hz), 7.65 (s, 1H), 7.48-7.45 (m, 1H), 7.35-7.30 (m, 4H), 7.28-7.24(m, 1H), 6.94(d, 1H, J=6.1 Hz), 3.79 (s, 3H), 3.75 (s, 2H). MS (m/z):502.1 (M+H) (found).

Example 238N-(3-Fluoro-4-(2-(1-methyl-1H-imidazol-5-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamoyl)-2-phenylacetamide (307)3-Fluoro-4-[2-(1-methyl-1H-imidazol-5-yl)-thieno[3,2-b]pyridin-7-yloxy]-phenylamine(306)

Starting from the compound 98 (scheme 19) and following the proceduresdescribed above for the synthesis of compound 12 (scheme 2, steps 1-4)but replacing 2-bromothiazole at the Stille coupling stage with5-bromo-1-methyl-1H-imidazole (Table 9), title compound 306 wasobtained. MS (m/z): 341.0M+H) (found).

N-(3-Fluoro-4-(2-(1-methyl-1H-imidazol-5-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamoyl)-2-phenylacetamide (307)

A mixture of 306 (99 mg, 0.29 mmol) and 2-phenylacetyl isocyanate (97mg, 0.60 mmoL) [A. J. Hill et al. JACS, 62; 1940; 1595] was stirred for1 h at room temperature, loaded directly onto a flash chromatographycolumn and gradient eluted with EtOAc, to MeOH/EtOAc (10:90) to affordthe title compound 307 (42% yield) as a white solid. ¹H NMR (d-DMSO) δ(ppm): 11.11 (s, 1H), 10.68 (s, 1H, J=5.5 Hz), 8.49(d), 7.85 (s, 1H),7.82(dd, 1H, J₁=12.9 Hz, J₂=2.4 Hz), 7.76 (s, 1H), 7.43 (m, 2H), 7.40(s, 1H), 7.32 (m, 4H), 7.28 (m, 1H), 6.61(d, 1H, J=5.5 Hz), 3.89 (s,3H), 3.74 (s, 2H). MS (m/z): 502.4 (M+H) (found).

Example 239N-(4-(2-(1-Ethyl-1H-imidazol-4-yl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenylcarbamoyl)-2-phenylacetamide (309a)4-[2-(1-Ethyl-1H-imidazol-4-yl)-thieno[3,2-b]pyridin-7-yloxy]-3-fluoro-phenylamine(308)

Starting from the compound 98 (scheme 19) and following the proceduresdescribed above for the synthesis of compound 12 (scheme 2, steps 1-4)but replacing 2-bromothiazole at the Stille coupling stage with4-bromo-1-ethyl-1H-imidazole (Table 9), title compound 308 was obtained.MS (m/z): 355.1 (M+H) (found).

N-(4-(2-(1-Ethyl-1H-imidazol-4-yl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenylcarbamoyl)-2-phenylacetamide (309a)

A mixture of 308 (300 mg, 0.85 mmol) and 2-phenylacetyl isocyanate (164mg, 1.02 mmoL) [Arthur J. Hill et al. JACS, 62; 1940; 1595] was stirredfor 1 h at room temperature, loaded directly onto a flash chromatographycolumn and gradient eluted with EtOAc, to MeOH/EtOAc (20:80) to affordthe title compound 309a (45% yield) as a white solid. ¹H NMR (d-DMSO) δ(ppm): 11.07 (s, 1H), 10.63 (s, 1H), 8.41(d, 1H, J=5.5 Hz), 7.94(d, 1H,J=1.4 Hz), 7.80(dd, 1H, J₁=13.1 Hz, J₂=2.4 Hz), 7.77(d, 1H, J=1.1 Hz),7.65 (s, 1H), 7.46-7.39 (s, 2H), 7.35-7.19 (m, 4H), 7.28-7.24 (m, 1H),6.54(dd, 1H, J₁=5.5 Hz, J₂=0.8 Hz), 4.03(q, 2H), 3.73 (s, 2H), 1.38(t,3H). MS (m/z): 516.1 (M+H) (found).

Example 240N-(4-(2-(1-Ethyl-1H-imidazol-4-yl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenylcarbamoyl)-2-(2-fluorophenyl)acetamide (309b)

A mixture of 308 (320 mg, 0.90 mmol) and (2-fluoro-phenyl)-acetylisocyanate (600 mg, 3.35 mmoL) [A. J. Hill et al. JACS, 62; 1940; 1595]was stirred for 1 h at room temperature, loaded directly onto a flashchromatography column and gradient eluted with EtOAc, to MeOH/EtOAc(20:80), to afford the title compound 309b in 42% yield as a whitesolid. ¹H NMR (d-DMSO) δ (ppm): 11.10 (s, 1H), 10.58 (s, 1H), 8.42(d,1H, J=5.5 Hz), 7.94(d, 1H, J=1.1 Hz), 7.82-7.77 (m, 2H), 7.65 (s, 1H),7.45-7.30 (m, 4H), 7.19-7.16 (m, 2H), 6.54(dd, 1H, J₁=0.7 Hz, J₂=5.4Hz), 4.04(q, 2H), 3.83 (s, 2H), 1.38(t, 3H). MS (m/z): 534.1 (M+H)(found).

Example 241N-(4-(2-(1-Ethyl-1H-imidazol-4-yl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenylcarbamoyl)-2-(2-methoxyphenyl)acetamide (309c)

A mixture of 308 (370 mg, 1.05 mmol) and (2-methoxy-phenyl)-acetylisocyanate (240 mg, 1.25 mmoL) [A. J. Hill et al. JACS, 62; 1940; 1595]was stirred for 1 h at room temperature, loaded directly onto a flashchromatography column and eluted with EtOAc, to afford the titlecompound 309c in 42% yield as a white solid. ¹H NMR (d-DMSO) δ (ppm):10.98 (s, 1H), 10.69 (s, 1H), 8.41(d, 1H, J=5.3 Hz), 7.94(d, 1H, J=1.2Hz), 7.81(dd, 1H, J₁=13.1 Hz, J₂=2.4 Hz), 7.77(d, 1H, J=0.9 Hz), 7.65(s, 1H), 7.45-7.40 (m, 2H), 7.26-7.19 (m, 2H), 6.97(d, 1H, J=8.0 Hz),6.89(dt, 1H, J₁=0.8 Hz, J₂=8.2 Hz), 6.54(d, 1H, J=5.5 Hz), 4.04(q, 2H),3.75 (s, 3H), 3.70 (s, 2H), 1.38(t, 3H). MS (m/z): 546.1 (M+H) (found).

Example 2421-{4-[2-(1-Ethyl-1H-imidazol-4-yl)-thieno[3,2-b]pyridin-7-yloxy]-3-fluoro-phenyl}-3-[2-(2-fluoro-phenyl)-acetyl]-thiourea(310a)

To a suspension of the 308 (385 mg, 0.99 mmol) in THF (10 mL) was added2-(2-fluorophenyl)acetyl isothiocyanate (263 mg, 1.49 mmol) and thereaction mixture was stirred for 1 hr, transferred onto a flashchromatography column and eluted with EtOAc/MeOH 19:1, to afford titlecompound 310a (366.9 mg, 67% yield) as a creamy solid. ¹HNMR: (DMSO-d₆)δ (ppm): 12.42 (s, 1H), 11.87 (s, 1H), 8.44 (d, J=5.5 Hz, 1H), 8.02 (d,J=11.5 Hz, 1H), 7.95 (s, 1H), 7.78 (s, 1H), 7.67 (s, 1H), 7.52 (m, 2H),7.42 (m, 2H), 7.25 (m, 2H), 7.06 (d, J=5.5 Hz, 1H), 4.04 (q, J=7.3 Hz,2H), 3.92 (s, 2H), 7.4 (t, J=7.3 Hz, 3H). MS (m/z): 550.0 (M+1).

Example 2431-{4-[2-(1-Ethyl-1H-imidazol-4-yl)-thieno[3,2-b]pyridin-7-yloxy]-3-fluoro-phenyl}-3-[2-(2-methoxy-phenyl)-acetyl]-thiourea(310b)

Starting from the compound 308, following the procedure described abovefor the synthesis of 310a but replacing 2-(2-fluorophenyl)acetylisothiocyanate with (2-methoxy-phenyl)-acetyl isothiocyanate, titlecompound 310b was obtained in 82% yield. ¹H NMR (DMSO-d₆) δ (ppm): 12.57(s, 1H), 11.76 (s, 1H), 8.45 (d, J=5.5 Hz, 1H), 8.07 (m, 1H), 7.96 (d,J=1 Hz, 1H), 7.79 (d, J=1 Hz, 1H), 7.69 (s, 1H), 7.6 (m, 2H), 7.26 (m,2H), 7.0 (d, J=7.4 Hz, 1H), 6.92 (m, 1H), 6.59 (d, J=5.5 Hz, 1H), 4.06(q, J=7.5 Hz, 2H), 3.82 (s, 2H), 3.79 (s, 3H), 1.4 (t, J=7.4 Hz, 3H). MS(m/z): 562.0 (M+1).

Example 244

N-Ethyl-7-(2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)-N-methylthieno[3,2-b]pyridine-2-carboxamide(311)

Title compound 311 was obtained by following the procedures describedabove for the synthesis of compound 8a (scheme 1, example 1) butreplacing dimethylamine in the step 4 with N-methylethanamine. ¹H NMR(400 MHz, DMSO-d6) (ppm) 12.49 (s, 1H), 11.82 (s, 1H), 8.64 (d, J=5.48Hz, 1H), 8.03 (d, J=12.7 Hz, 1H) 7.85 (m, 1H), 7.54 (m, 2H), 7.32 (m,4H), 7.24 (m, 1H), 6.82 (d, J=5.3 Hz, 1H), 3.83 (s, 2H), 3.53 (m, 2H),3.38 (m, 2H), 3.05 (s, 1H), 1.10 m, 3H). MS (calcd.) 522.1, found 523.2(M+H).

Example 245

N-(4-(2-(4-(Dimethylamino)phenyl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenylcarbamothioyl)-2-phenylacetamide(312)

Title compound 312 was obtained by following the procedures describedabove for the synthesis of compound 50 (scheme 10, example 55) butreplacing4,4,5,5-tetramethyl-2-(4-(methylsulfonyl)phenyl)-1,3,2-dioxaborolane inthe first step with 4-(dimethylamino)phenylboronic acid. ¹H NMR (DMSO):12.48 (1H, s), 11.83 (1H, s), 8.44 (1H, d, J=5.48 Hz), 7.99 (1H, d,J=12.91 Hz), 7.77 (1H, s), 7.68 (2H, d, J=8.41 Hz), 7.51 (2H, br),7.33-7.28 (5H, m), 6.77 (2H, d, J=8.22 Hz), 6.56 (1H, d, J=4.89 Hz),3.81 (2H, s), 2.96 (6H, s), MS: calcd: 556.7, found: 556.9 (M+H).

Example 246

N-(3-Fluoro-4-(2-(3-(morpholinomethyl)phenyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(313)

Title compound 313 was obtained by following the procedures describedabove for the synthesis of compound 75 (scheme 15) but starting from4-(3-bromobenzyl)morpholine instead of tert-butyl3-bromobenzyl(2-methoxyethyl)carbamate (65). ¹H NMR (DMSO): 12.49 (1H,s), 11.84 (1H, s), 8.52 (1H, d, J=5.48 Hz), 8.05 (1H, s), 8.01 (1H, d,J=12.72 Hz), 7.79-7.78 (2H, m), 7.53 (2H, br), 7.46 (1H, t, J=7.63 Hz),7.39 (1H, d, J=7.63 Hz), 7.34-7.26 (5H, m), 6.66 (1H, d, J=5.28 Hz),3.82 (2H, s), 3.57 (4H, br), 3.32 (2H, s), 2.38 (4H, br). MS calcd:612.7, found: 613.3 (M+1).

Example 247

N-(3-Fluoro-4-(thieno[3,2-d]pyrimidin-4-yloxy)phenylcarbamothioyl)-2-phenylacetamide(314)

Title compound 314 was obtained by following the procedures describedabove for the synthesis of compound 173 (scheme 34, example 135) butreplacing 3-chloro-4-nitrophenol in the step 1 with2-fluoro-4-nitrophenol. ¹HNMR (DMSO-d₆) δ (ppm): 12.42 (bs, 1H), 11.79(bs, 1H), 8.71 (s, 1H), 8.51 (d, J=5.2 Hz, 1H), 7.91 (dd, J=2.4 and 12.0Hz, 1H), 7.70 (d, J=5.2 Hz, 1H), 7.53 (dd, J=8.4 Hz, 1H), 7.47 (dd,J=2.4 and 8.4 Hz, 1H), 7.38-7.30 (m, 4H), 7.30-7.27 (m, 1H), 3.82 (s,2H). LRMS: 438.1(calc) 439.1 (found).

Example 248

N-(3-Fluoro-4-(thieno[2,3-d]pyrimidin-4-yloxy)phenylcarbamothioyl)-2-phenylacetamide(315)

Title compound 315 was obtained starting from the compound 205 (scheme44) and following the procedures described above for the synthesis ofcompound 314. ¹HNMR (DMSO-d₆) δ (ppm): 12.42 (s, 1H), 11.80 (s, 1H),8.63 (s, 1H), 8.01 (d, J=5.6 Hz, 1H), 7.91 (dd, J=2.0 and 12.0 Hz, 1H),7.70 (d, J=5.6 Hz, 1H), 7.50 (t, J=8.4 Hz, 1H), 7.46 (dd, J=2.4 and 8.4Hz, 1H), 7.36-7.30 (m, 4H), 7.30-7.24 (m, 1H), 3.82 (s, 2H). LRMS: 438.4(calc) 439.3 (found).

Example 249

N-(4-(5H-Pyrrolo[3,2-d]pyrimidin-4-yloxy)-3-fluorophenylcarbamothioyl)-2-phenylacetamide(316)

Title compound 316 was obtained by following the procedures describedabove for the synthesis of compound 31a (scheme 5, example 28) butskipping N-methylation step. ¹HNMR (DMSO-d₆) δ(ppm): 12.41 (s, 1H), 8.32(s, 1H), 7.91 (d, J=10 Hz, 1H), 7.48 (s, 1H), 7.56-7.42 (m, 2H),7.39-7.32 (m, 4H), 7.30-7.22 (m, 1H), 6.66 (s, 1H), 3.83 (s, 2H). LRMS:421.1 (calc) 422.1 (found).

2-(2-Ethynylphenyl)acetyl isothiocyanate (317) Step 1: Methyl2-(2-iodophenyl)acetate (318)

A solution of 2-iodophenylacetic acid (5.05 g, 19.3 mmol) and sulfuricacid (0.5 mL) in methanol was heated under reflux for 6 h, then cooledand concentrated under reduced pressure. The residue was partitionedbetween ethyl acetate and water, organic phase was collected, washedwith 1M NaOH, brine, dried (MgSO₄), filtered and concentrated to affordpure 318 (5.05 g, 95% yield). ¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.85 (dd,J=8.0, 1.2 Hz, 1H); 7.34-7.27 (m, 2H); 6.97 (dt, J=7.6, 2.2 Hz, 1H);3.81 (s, 2H); 3.73 (s, 3H).

Step 2: Methyl 2-(2-((trimethylsilyl)ethynyl)phenyl)acetate (319)

To a solution of ester 318 (7.50 g, 27.2 mmol) in dry DME (125 mL) at 0°C. was added triethylamine (6.0 mL, 4.3 g, 43 mmol), copper (I) iodide(1.00 g, 5.25 mmol), and bis(triphenylphosphine) palladium (II) chloride(0.65 g, 0.93 mmol). The mixture was degassed with a stream of N₂ for 5min, then trimethylsilylacetylene (5.8 mL, 4.1 g, 41 mmol) was added andthe reaction mixture was warmed to room temperature and stirred for 24h. It was concentrated under reduced pressure, partitioned between ethylacetate and water, washed with brine, dried (anhydrous MgSO₄), filteredand concentrated. Flash chromatography of the residue (eluent 4% ethylacetate/hexanes) afforded title compound 319 (4.65 g, 69% yield). ¹H NMR(400 MHz, CDCl₃) δ (ppm): 7.22 (dd, J=7.4, 0.8 Hz, 1H); 7.07-6.95 (m,3H); 3.58 (s, 2H); 3.45 (s, 3H); 0.00 (s, 9H). LCMS: (M+H) 247.1.

Step 3: 2-(2-Ethynylphenyl)acetic acid (320)

To a solution of ester 319 (4.65 g, 18.9 mmol) in 1:1 THF/methanol (100mL) was added lithium hydroxide monohydrate (1.60 g, 38.1 mmol) in water(25 mL) and the mixture was stirred at r.t. for 30 min. It was thenpartially concentrated, the aqueous residue was washed with ether, thenacidified with 3M HCl (aq) and extracted with ethyl acetate. The organicextract was washed with water, dried (anhydrous MgSO₄), filtered andconcentrated. The residue was dissolved in ethyl acetate, run through ashort plug of silica gel, and concentrated to provide 320 (2.77 g, 92%yield). ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.40 (br s, 1H); 7.45 (d,J=8.0 Hz, 1H), 7.37-7.24 (m, 3H), 4.36 (s, 1H); 3.72 (s, 2H). LCMS:(M+Na) 183.1

Step 4: 2-(2-Ethynylphenyl)acetyl isothiocyanate (317)

To acid 319 (0.34 g, 2.1 mmol) in dry dichloromethane (25 mL) was addedoxalyl chloride (0.39 mL, 0.57 g, 4.5 mmol) and dry DMF (0.05 mL). Themixture was stirred for 1 h, then concentrated under reduced pressure.The residue was re-dissolved in toluene (40 mL) and lead thiocyanate(0.75 g, 2.3 mmol) was added. The resulting suspension was heated toreflux with vigorous stirring for 3 h, then cooled, filtered throughcelite, and concentrated to afford crude 317 which was used withoutfurther purification.

2-(2-Ethynyl-4-fluorophenyl)acetyl isothiocyanate (321) Step 1:1-(Bromomethyl)-4-fluoro-2-iodobenzene (322)

N-Bromosuccinimide (0.61 g, 3.4 mmol) and VAZO (0.10 g, 0.41 mmol) wereadded to a solution of 4-fluoro-2-iodotoluene (0.75 g, 3.2 mmol) incarbon tetrachloride (45 mL). The resulting suspension was stirred andheated under reflux for 18 hours. It was then cooled and filtered, thesolid was rinsed with carbon tetrachloride (5 mL), and the combinedfiltrates were concentrated under reduced pressure. The residue waspurified by flash column chromatography (eluting with hexanes) toprovide 322 (0.58 g, 58% yield). ¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.51(dd, J=8.0, 2.5 Hz, 1H); 7.38 (dd, J=8.4, 5.7 Hz, 1H); 7.00 (dt, J=8.2,2.7 Hz, 1H); 4.54 (s, 2H).

Steps 2-3: 2-(4-Fluoro-2-iodophenyl)acetic acid (324)

To the benzylic bromide 322 (4.90 g, 15.6 mmol) in ethanol (50 mL) wasadded sodium cyanide (1. 60 g, 32.6 mmol) in water (10 mL) and themixture was heated to reflux for 3 h. It was then concentrated,partitioned between diethyl ether and water; organic phase wascollected, washed with brine, dried (MgSO₄), filtered and concentratedto afford crude nitrile 323. To this material in 1:1 THF/methanol (50mL) was added lithium hydroxide monohydrate (1.75 g, 41.7 mmol), inwater (12 mL) and the mixture was heated to reflux for 24 h. It was thencooled, partially concentrated and the aqueous residue was washed withether, then acidified with 3M HCl (aq) and extracted with ether. Theextract was washed with brine, dried (MgSO₄), filtered and concentratedto yield acid 324 (3.95 g, 90% yield over two steps). LCMS: (M+Na)303.0.

Step 4: Methyl 2-(4-fluoro-2-iodophenyl)acetate (325)

A solution of the acid 324 (3.95 g, 14.1 mmol) and sulfuric acid (0.5mL) in methanol (50 mL) was heated under reflux for 18 h, then cooledand concentrated under reduced pressure. The residue was partitionedbetween ethyl acetate and water; the organic phase was collected, dried(anhydrous MgSO₄), filtered and concentrated to afford pure 325 (3.93 g,95% yield). ¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.57 (dd, J=8.2, 2.7 Hz,1H); 7.25 (dd, J=8.6, 5.9 Hz, 1H); 7.05 (dt, J=8.2, 2.7 Hz, 1H); 3.78(s, 2H); 3.72 (s, 3H). LCMS: (M+H) 295.0.

Step 5: Methyl 2-(4-fluoro-2-((trimethylsilyl)ethynyl)phenyl)acetate(326)

To a solution of ester 325 (3.80 g, 12.9 mmol) in dry DME (100 mL) at 0°C. was added triethylamine (4.5 mL, 3.3 g, 33 mmol), copper (I) iodide(0.50 g, 2.6 mmol), and bis(triphenylphosphine) palladium (II) chloride(0.38 g, 0.54 mmol). The mixture was degassed with a stream of N₂ for 5min, then trimethylsilylacetylene (4.0 mL, 2.8 g, 29 mmol) was added andthe reaction mixture was warmed to room temperature and stirred for 3 h.It was then concentrated under reduced pressure, re-dissolved in ether,filtered and concentrated. Silica gel chromatography of the residue(eluent 10% ethyl acetate/hexanes) afforded 326 (3.30 g, 97% yield). ¹HNMR (400 MHz, CDCl₃) δ (ppm): 7.23 (dd, J=8.6, 5.7 Hz, 1H); 7.14 (dd,J=9.0, 2.7 Hz, 1H); 7.00 (dt, J=8.4, 2.7 Hz, 1H); 3.79 (s, 2H); 3.70 (s,3H); 0.25 (s, 9H). LCMS: (M+H) 265.2.

Step 6. 2-(2-Ethynyl-4-fluorophenyl)acetic acid (327)

To a solution of ester 326 (3.30 g, 12.5 mmol) in 1:1 THF/methanol (100mL) was added lithium hydroxide monohydrate (1.60 g, 38.1 mmol) in water(25 mL) and the mixture was stirred at r.t. for 30 min. It was thenpartially concentrated; the aqueous residue was washed with ether; thenacidified with 3M HCl (aq), extracted with ethyl acetate. The organicextract was washed with water, dried (anhydrous MgSO₄), filtered andconcentrated to provide acid 327 (2.10 g, 95% yield). ¹H NMR (400 MHz,DMSO-d₆) δ (ppm): 7.36 (dd, J=8.6, 5.9 Hz, 1H); 7.30 (dd, J=9.2, 2.7 Hz,1H); 7.21 (dt, J=8.6, 2.7 Hz, 1H); 4.48 (s, 1H); 3.70 (s, 2H). LCMS:(M+Na) 201.1.

Step 7: 2-(2-Ethynyl-4-fluorophenyl)acetyl isothiocyanate (321)

To a solution of acid 327 (2.10 g, 11.8 mmol) in dry dichloromethane (50mL) was added oxalyl chloride (2.0 mL, 2.9 g, 23 mmol) and dry DMF (0.1mL). The mixture was stirred for 1 h, then concentrated under reducedpressure. The residue was re-dissolved in toluene (75 mL) and leadthiocyanate (4.0 g, 12 mmol) was added. The resulting suspension washeated to reflux with vigorous stirring for 3 h, then cooled, filteredthrough celite, and concentrated to afford crude 321 which was usedwithout further purification.

2-(2-Ethynyl-6-fluorophenyl)acetyl isothiocyanate (328) Step 1.2-(2-Bromo-6-fluorophenyl)acetonitrile (329)

A suspension of 2-bromo-6-fluorotoluene (5.00 g, 26.45 mmol), NBS (5.18g, 29.10 mmol), and VAZO (323 mg, 1.32 mmol) in CCl₄ (100 mL) was heatedto reflux under vigoroue stirring overnight. The reaction mixture wascooled to room temperature, concentrated and the residue was removed byfiltration. The filtrate was concentrated and the residue wasre-dissolved in ethanol (90 mL), treated with a solution of NaCN (2.59g, 52.9 mmol) in water (20 mL) and the combined mixture was heated toreflux for 5 hrs. Ethanol was removed under reduced pressure, theaqueous residue was diluted with water and extracted with AcOEt. Theorganic layer was successively washed with water and brine,concentrated, adsorbed on silica gel and purified by flash columnchromatography (eluents AcOEt/hexanes: 10/90 to 20/80) to afford titlecompound 329 (3.92 g, 69% yield over 2 steps, slightly contaminated) asa pale yellow sticky solid. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 7.62-7.57(m, 1H), 7.45-7.35 (m, 2H), 4.08 (s, 2H).

Step 2. Ethyl 2-(2-bromo-6-fluorophenyl)acetate (330)

A solution of 329 (3.89 g, 18.17 mmol) and concentrated sulfuric acid(35 mL) in ethanol (80 mL) was heated to reflux overnight. The mixturewas allowed to cool down to room temperature, and poured into a mixtureof ice/water, shaken for 15 min, and extracted with AcOEt. The extractwas successively washed with water, sat. NaHCO₃, water, dried overanhydrous magnesium sulfate, filtered, and concentrated to afford titlecompound 330 (4.86 g, quantitative yield, contaminated) as a yellow oilyliquid. LCMS: 261.0 and 263.0 (M+H)⁺.

Step 3. Ethyl 2-(2-fluoro-6-((trimethylsilyl)ethynyl)phenyl)acetate(331)

To a solution of 330 (4.85 g, 18.0 mmol) in anhydrous THF (100 ml) wereadded Pd(PPh₃)₂Cl₂ (632 mg, 0.9 mmol), CuI (343 mg, 1.8 mmol),TMSacetylene (3.24 mL, 23.4 mmol), respectively. The reaction mixturewas degassed for 15 min with nitrogen, treated with Et₃N (7.53 mL, 54mmol), stirred overnight under nitrogen and diluted with AcOEt. TheAcOEt solution was successively washed with sat.NH₄Cl, dried overanhydrous MgSO₄, filtered, and concentrated. The crude product waspurified by flash column chromatography (eluents AcOEt/hexanes: 2/98 to10/90) to afford a mixture of 331 and 330 which was resubmitted to thesame reaction conditions and work-up. The crude product was purifiedthree times by flash column chromatography (eluents AcOEt/hexanes: 2/98)to afford title compound 331 (611 mg, 12% yield over 2 steps, slightlycontaminated) as a brown oily liquid. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm):7.38-7.25 (m, 3H), 4.09 (q, J=7.2 Hz, 2H), 3.83 (d, J=7.8 Hz, 1H), 3.82(d, J=7.4 Hz, 1H), 1.18 (t, J=7.0 Hz, 3H), 0.23 (s, 9H).

Step 4. 2-(2-Ethynyl-6-fluorophenyl)acetic acid (332)

A stirred solution of 331 (607 mg, 2.18 mmol) and IN NaOH (5.5 mL) inmethanol (15 mL) was heated at 45° C. for 16 h under nitrogen. Thereaction mixture was allowed to cool to room temperature; it was thenconcentrated, diluted with water, and washed with hexanes. The aqueouslayer was collected, acidified with 3N HCl and extracted twice withAcOEt. The organic extract was dried over anhydrous magnesium sulfate,filtered, and concentrated to afford title compound 332 (400 mg, 94%yield, mono-hydrate) as an orange sticky solid. LCMS: 201.1 (M+Na)⁺.

Step 5. 2-(2-Ethynyl-6-fluorophenyl)acetyl isothiocyanate (328)

To a stirred solution at 0° C. of 332 (390 mg, 2.19 mmol) in anhydrousCH₂Cl₂ (25 ml) were added oxalyl chloride (420 μL, 4.82 mmol) andanhydrous DMF (few drops). The reaction mixture was stirred undernitrogen at 0° C. for 40 min, and then at room temperature for 1 hr,concentrated and dried under high vacuum. The solid residue wasdissolved in anhydrous toluene (50 mL) and Pb(NCS)₂ was added (780 mg,2.41 mmol). The suspension was heated to reflux for 3.5 hrs undernitrogen, cooled to room temperature, filtered through celite, andrinsed with AcOEt. The filtrate was concentrated and dried under highvacuum to afford title compound 328 (474 mg, 98% yield) as a dark brownoily liquid.

2-(2-(1-Fluorovinyl)phenyl)acetyl isothiocyanate (333) Step 1:2-(2-(1-Fluorovinyl)phenyl)acetic acid (335)

A suspension of methyl 2-(2-(1-fluorovinyl)phenyl)acetate (334, 770.8mg, 4.015 mmol) (Hakamoto T.; Kobavashi T. J. Org. Chem. 2003, 68,6354-6359) and LiOH×H₂O (185 mg, 4.41 mmol) in H₂O/THF (1:1, 11 mL) wasstirred overnight at room temperature. The THF was evaporated off underreduced pressure; the aqueous residue was diluted with water, washedwith EtOAc, acidified to pH˜3 by addition of 1N HCl and extracted withDCM. The organic extract was dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure affording 335 (557.2 mg, 77% yield)as a white solid. LCMS: (M−1) 187.1 (100%).

Step 2: 2-(2-(1-Fluorovinyl)phenyl)acetyl isothiocyanate (333)

To a solution of 2-(2-(1-fluorovinyl)phenyl)acetic acid (335, 557.2 mg,3.9 mmol) in DCM (6.2 mL) oxalyl chloride (810 mL, 9.28 mmol) was addedin one portion followed by one drop DMF. The mixture was stirred untilno more bubbling occurred (˜1 h), then concentrated under reducedpressure. The residue was re-dissolved in toluene (30.9 mL), Pb(NCS)₂(999.6 mg, 3.09 mmol) was added and the mixture was heated to refluxunder vigorous stirring for 3 h. The suspension was filtered throughCelite®, the Celite® washed with toluene and the combined filtrates wereconcentrated under reduced pressure affording title compound 333 630.3mg, 92% yield) as a red syrup that was used in the next step withoutfurther purification. LCMS: (M+MeOH+1) 254.1 (40%).

Isothiocyanates 336-339 were synthesized similarly to theisothiocyanates 317, 321 and 328 (schemes 75-77). Compound 340 wasprepared similarly to 333 (scheme 78).

TABLE 24 Characterization of compounds 339–375 (examples 250–284)prepared according to the procedures similar to ones shown in theschemes 2, 17, 18, 20, 35, 49, 73 and 74. Cpd Ex. StructureCharacterization 341 250

¹H NMR(400 MHz, DMSO-d₆) δ (ppm): 12.38(s, 1H); 11.87(s, 1H); 8.54(d,J=5.5 Hz, 1H); 8.03(d, J=12.5 Hz, 1H); 7.83(s, 1H); 7.54–7.43(m, 4H);7.25(dd, J=9.8, 2.7 Hz, 1H); 7.08(dd, J=8.6, 2.7 Hz, 1H); 7.07 (s, 1H);6.69(d, J=5.7 Hz, 1H); 4.37(q, J= 7.2 Hz, 2H); 3.92(s, 2H); 1.42(t,J=7.2 Hz, 3H). LCMS: (M + H) 568.1.2-(2,4-Difluorophenyl)-N-(4-(2-(1-ethyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenylcarbamothioyl)acetamide 342 251

¹H NMR(400 MHz, DMSO-d₆) δ (ppm): 12.48(s, 1H); 11.83(s, 1H); 8.54(d,J=5.5 Hz, 1H); 8.05–8.01(m, 1H); 7.85(s, 1H); 7.55–7.51(m, 2H); 7.49(s,1H); 7.39–7.35 (m, 2H); 7.20–7.15(m, 2H); 7.09(s, 1H); 6.69(d, J=5.3 Hz,1H); 4.37(q, J=7.2 Hz, 2H); 3.82(s, 2H); 1.42(t, J=7.2 Hz, 3H). LCMS:(M + H) 550.2 N-(4-(2-(1-Ethyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenylcarbamothioyl)-2-(4-fluorophenyl)acetamide 343 252

¹H NMR(400 MHz, DMSO-d₆) δ (ppm): 12.53(s, 1H); 11.90(s, 1H); 8.54(s,J=5.9 Hz, 1H); 8.06(d, J=11.9 Hz, 1H); 7.83(s, 1H); 7.58–7.52(m, 2H);7.50–7.48(m, 2H); 7.40–7.38(m, 2H); 7.33–7.27(m, 1H); 7.07 (s, 1H);6.69(d, J=5.3 Hz, 1H); 4.44(s, 1H); 4.37(q, J=7.4 Hz, 2H); 4.05(s, 2H);1.42(t, J=7.4 Hz, 3H). LCMS: (M + H) 556.2N-(4-(2-(1-Ethyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenylcarbamothioyl)-2-(2-ethynylphenyl)acetamide 344 253

¹H NMR(400 MHz, DMSO-d₆) δ (ppm): 12.47(s, 1H); 11.90(s, 1H); 8.52(d,J=5.9 Hz, 1H); 8.06(dd, J=12.5, 2.3 Hz, 1H); 7.97 (s, 1H); 7.89(s, 1H);7.74(s, 1H); 7.59–7.51 (s, 2H); 7.43(dd, J=8.6, 5.9 Hz, 1H); 7.35 (dd,J=9.2, 2.8 Hz, 1H); 7.26(dt, J=8.8, 2.7 Hz, 1H); 6.69(d, J=5.5 Hz, 1H);4.57(s, 1H); 4.02(s, 2H); 3.73(s, 3H). LCMS: (M + H) 560.1.2-(2-ethynyl-4-fluorophenyl)-N-(3-fluoro-4-(2-(1-methyl-1H-imidazol-4-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)acetamide 345 254

¹H NMR(400 MHz, DMSO-d₆) δ (ppm): 12.47(s, 1H); 11.90(s, 1H); 8.53(d,J=5.9 Hz, 1H); 8.10–8.02(m, 3H); 7.75(s, 1H); 7.59–7.5 1(m, 2H);7.43(dd, J=8.8, 7.3 Hz, 1H); 7.35(dd, J=8.8, 2.9 Hz, 1H); 7.26(dt, J=8.8, 2.7 Hz, 1H); 6.71(d, J=5.5 Hz, 1H); 4.57(s, 1H); 4.08(q, J=7.2 Hz,2H); 4.03(s, 2H); 1.40(t, J=7.4 Hz, 3H). LCMS:(M + H) 574.1N-(4-(2-(1-ethyl-1H-imidazol-4-yl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenylcarbamothioyl)-2-(2-ethynyl-4-fluorophenyl)acetamide 346 255

¹H NMR(400 MHz, DMSO-d₆) δ (ppm): 12.34(s, 1H), 11.89(s, 1H), 8.44(d,J=5.48 Hz, 1H), 8.02(m, 1H), 7.94(s, 1H), 7.77(s, 1H), 7.67(s, 1H),7.51(m, 2H), 7.36(m, 3H), 6.57(d, J=5.48 Hz, 1H), 4.31(s, 1H), 4.03 (q,J=7.24 Hz, 2H), 3.94(s, 2H), 1.39(t, J= 7.43 Hz, 3H). LCMS: 574.2(M +H). N-(4-(2-(1-ethyl-1H-imidazol-4-yl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenylcarbamothioyl)-2-(4-ethynyl-3-fluorophenyl)acetamide 347 256

¹H NMR(400 MHz, DMSO-d₆) δ (ppm): 12.51(s, 1H), 11.90(s, 1H), 8.53(d,J=5.48 Hz, 1H), 8.18(s, 1H), 8.07(m, 1H), 7.90(s, 1H), 7.38(m, 6H),7.04(s, 1H), 6.68(d, J= 5.48 Hz, 1H), 4.45(s, 1H), 4.05(s, 2H), 3.99 (s,3H). LCMS: 542.2(M + H). (formate salt)2-(2-ethynylphenyl)-N-(3-fluoro-4-(2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)acetamide 348 257

¹H NMR(400 MHz, DMSO-d₆) δ (ppm): 12.47(s, 1H), 11.85(s, 1H), 8.54(d,J=5.48 Hz, 1H), 8.02(s, 1H), 7.91(s, 1H), 7.42(m, 7H), 7.06(s, 1H),6.69(d, J=5.48 Hz, 1H), 4.17(s, 1H), 3.99(s, 3H), 3.86(s, 2H). LCMS:542.1(M + H). 2-(4-ethynylphenyl)-N-(3-fluoro-4-(2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)acetamide 349 258

¹H NMR(400 MHz, DMSO-d₆) δ (ppm): 12.37(s, 1H), 11.90(s, 1H), 8.53(d,J=5.48 Hz, 1H), 8.16(s, 1H), 8.01(m, 1H), 7.89(s, 1H), 7.54(m, 2H),7.31(m, 4H), 7.03(s, 1H), 6.68(d, J=5.48 Hz, 1H), 4.31(s, 1H), 3.98(s,3H), 3.94(s, 2H). LCMS: 560.2 (M + H). (formate salt)2-(4-ethynyl-3-fluorophenyl)-N-(3-fluoro-4-(2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)acetamide 350 259

¹H NMR(400 MHz, DMSO-d₆) δ (ppm): 12.47(s, 1H), 11.89(s, 1H), 8.44(d,J=5.48 Hz, 1H), 8.05(m, 1H), 7.89(s, 1H), 7.37(s, 6H), 7.03(s, 1H),6.67(d, J=5.48 Hz, 1H), 4.58(s, 1H), 4.03(s, 2H), 3.98(s, 3H). LCMS:560.2(M + H). 2-(2-ethynyl-4-fluorophenyl)-N-(3-fluoro-4-(2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)acetamide 351 260

¹H NMR(400 MHz, DMSO-d₆) δ (ppm): 12.48(s, 1H), 11.90(s, 1H), 8.52(m,1H), 8.02(m, 1H), 7.89(s, 1H), 7.48(m, 4H), 7.40 (s, 1H), 7.23(t, J=9Hz, 1H), 7.03(s, 1H), 6.69(d, J=5.48 Hz, 1H), 4.20(s, 1H), 3.98 (s, 3H),3.92(s, 2H). LCMS: 560.1(M + H).2-(5-ethynyl-2-fluorophenyl)-N-(3-fluoro-4-(2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)acetamide 352 261

¹H NMR(400 MHz, DMSO-d₆) δ (ppm): 12.42(s, 1H), 11.90(s, 1H), 8.54(m,1H), 8.06(m, 1H), 7.91(s, 1H), 7.47(m, 4H), 7.23 (m, 1H), 7.09(m, 2H),6.67(m, 1H), 4.0(s, 3H), 3.92(s, 2H). LCMS: 554.1(M + H).2-(2,4-difluorophenyl)-N-(3-fluoro-4-(2-(1-methyl1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)acetamide 353 262

¹H NMR(400 MHz, DMSO-d₆) δ (ppm): 12.53(s, 1H), 11.83(s, 1H), 8.53(d,J=5.28 Hz, 1H), 8.04(m, 1H), 7.90(s, 1H), 7.55(m, 2H), 7.41(s, 1H),7.19(m, 4H), 7.05(s, 1H), 6.68(d, J=5.28 Hz, 1H), 3.99(s, 3H), 3.87 (s,2H). LCMS: 532.2(M + H). N-(3-fluoro-4-(2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7- yloxy)phenylcarbamothioyl)-2-o-tolylacetamide354 263

¹H NMR(400 MHz, DMSO-d₆) δ (ppm): 12.50(s, 1H), 11.84(s, 1H), 8.54(m,1H), 8.03(m, 1H), 7.91(s, 1H), 7.55(m, 2H), 7.41 (s, 3H), 7.17(m, 3H),7.05(s, 1H), 6.68(m, 1H), 3.99(s, 3H), 3.84(s, 2H). LCMS: 536.1 (M + H).N-(3-fluoro-4-(2-(1-methyl-1H-imidazol-2- yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-(4- fluorophenyl)acetamide 355 264

¹H NMR(400 MHz, DMSO-d₆) δ (ppm): 12.49(s, 1H), 11.84(s, 1H), 8.45(dd,J=5.2, 2.5 Hz, 1H), 8.06(d, J=12.5Hz, 1H), 7.87 (s, 1H), 7.72(s,1H),7.70(s, 1H), 7.67–7.36 (m, 6H), 6.59(dd, J=1.7, 3.7 Hz, 1H), 5.08 (ddd,J=3, 2.9, 28.9 Hz, 1H), 5.00(ddd, J= 3.3, 2.9, 62.4 Hz, 1H), 4.01(s,2H), 3.72(s, 3H). LCMS: 562.2(M + H)N-(3-fluoro-4-(2-(1-methyl-1H-imidazol-4- yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-(2-(1- fluorovinyl)phenyl)acetamide 356 265

¹H NMR(400 MHz, DMSO-d₆) δ (ppm): 12.47(s, 1H), 11.9(s, 1H), 8.45(d,J=5.5 Hz, 1H), 8.02(dd, J=2, 13.3 Hz, 1H), 7.87 (d, J=1.1 Hz, 1H),7.72(d, J=0.8 Hz, 1H), 7.69(s, 1H), 7.61-7.39(m, 6 H), 6.58(dd, J= 5.5Hz, J=0.8 Hz, 1H), 5.38(dd, J=3.9 Hz, J=52.2 Hz, 1H), 4.98(dd, J=3.9,19.0 Hz, 1H), 3.89(s, 2H), 3.72(s, 3H). LCMS: 562.2 (M + H)N-(3-fluoro-4-(2-(1-methyl-1H-imidazol-4- yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-(3-(1- fluorovinyl)phenyl)acetamide 357 266

¹H NMR(400 MHz, DMSO-d₆) δ (ppm): 12.4(br, 1H), 11.9(br, 1H), 8.46(d,J=5.5 Hz, 1H), 8.02(dd, J=11.8, 2.3 Hz, 1H), 7.87 (d, J=1.0 Hz, 1H),7.26(d, J=1Hz, 1H), 7.72(s, 1H), 7.69–7.48(m, 3H), 7.42–7.37 (m, 3H),6.58(dd, J=0.8, 5.5 Hz, 1H), 4.22 (s, 1H), 3.85(s, 2H), 3.72(s, 3H).LCMS: (M + H) 542.10 2-(3-ethynylphenyl)-N-(3-fluoro-4-(2-(1-methyl-1H-imidazol-4-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)acetamide 358 267

¹H NMR(400 MHz, DMSO-d₆) δ (ppm): 12.39(s, 1H), 11.91(s, 1H), 8.48(d,J=5.5 Hz, 1H), 8.04(dd, J=1.8, 12.1 Hz, 1H), 7.90 (d, J=1.8 Hz, 1H),7.76(s, 1H), 7.71(s, 1H), 7.59–7.46(m, 4H), 7.30(dd, J=8.6 Hz, 9.6 Hz,1H), 6.61(d, J=5.5 Hz, 1H), 4.21(s, 1H), 3.94(s, 2H), 3.73(s, 3H). LCMS:(M + H) 560.2 2-(5-ethynyl-2-fluorophenyl)-N-(3-fluoro-4-(2-(1-methyl-1H-imidazol-4-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)acetamide 359 268

¹H NMR(400 MHz, DMSO-d₆) δ (ppm): 12.51(s, 1H), 11.90(s, 1H), 8.46(d,J=5.4 Hz, 1H), 8.06(dd, J=12.4, 2.1 Hz, 1H), 7.87 (s, 1H), 7.72(s, 1H),7.69(s, 1H), 7.60–7.47 (m, 3H), 7.43–7.37(m, 2H), 7.35–7.28(m, 1H),6.59(d, J=5.5 Hz, 1H), 4.46(s, 1H), 4.06(s, 2H), 3.72(s, 3H). LCMS:542.1 (M + H)⁺. 2-(2-Ethynylphenyl)-N-(3-fluoro-4-(2-(1-methyl-1H-imidazol-4-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)acetamide 360 269

¹H NMR(400 MHz, DMSO-d₆) δ (ppm): 12.35(bs, 1H), 11.99(bs, 1H), 8.45(d,J= 5.5 Hz, 1H), 8.08–7.98(m, 1H), 7.87(d, J= 1.2 Hz, 1H), 7.72(d, J=1.0Hz, 1H), 7.69(s, 1H), 7.60–7.46(m, 2H), 7.41–7.27(m, 3H), 6.58(d, J=5.5Hz, 1H), 4.59(s, 1H), 4.09 (bs, 2H), 3.72(s, 3H). LCMS: 560.2 (M + H)⁺.2-(2-Ethynyl-6-fluorophenyl)-N-(3-fluoro-4-(2-(1-methyl-1H-imidazol-4-yl) thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)acetamide 361 270

¹H NMR(400 MHz, DMSO-d₆) δ (ppm): 12.40(s, 1H), 11.89(s, 1H), 8.46(d,J=5.6 Hz, 1H), 8.03(dd, J=12.8, 2.4 Hz, 1H), 7.87 (d, J=0.8 Hz, 1H),7.72(s, 1H), 7.69(s, 1H), 7.58–7.43(m, 3H), 7.26(td, J=10.0, 2.4 Hz,1H), 7.09(td, J=8.4, 2.0 Hz, 1H), 6.58(d, J= 5.6 Hz, 1H), 3.92(s, 2H),3.73(s, 3H). LCMS:(M + H) 554.12-(2,4-difluorophenyl)-N-(3-fluoro-4-(2-(1-methyl-1H-imidazol-4-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)acetamide 362 271

¹H NMR(400 MHz, DMSO-d₆) δ (ppm): 12.52(s, 1H), 11.83(s, 1H), 8.46(d,J=5.2 Hz, 1H), 8.05(dd, J=12.4, 2.4 Hz, 1H), 7.87 (d, J=1.2 Hz, 1H),7.72(d, J=1.2 Hz, 1H), 7.69(s, 1H), 7.58–7.48(m, 2H), 7.28–7.23 (m, 1H),7.22–7.13(m, 3H), 6.59(d, J=5.2 Hz, 1H), 3.88(s, 2H), 3.72(s, 3H),2.29(s, 3H). LCMS:(M + H) 532.2N-(3-fluoro-4-(2-(1-methyl-1H-imidazol-4- yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-o-tolylacetamide 363 272

¹H NMR(400 MHz, DMSO-d₆) δ (ppm): 12.44(s, 1H), 11.92(s, 1H), 8.65(d,J=6.0 Hz, 1H), 8.31(s, 1H), 8.26(s, 1H), 8.09(d, J= 13.3 Hz, 1H),7.85(s, 1H), 7.61–7.58(m, 2H), 7.47(q, J=7.6 Hz, 1H), 7.27 (td, J= 2.5,9.7 Hz, 1H), 7.01(td, J=2.5, 8.6 Hz, 1H), 6.88(d, J=5.9 Hz, 1H), 4.14(q,J=7.3 Hz, 2H), 3.93(s, 2H), 1.44(t, J=7.3 Hz, 3H). LCMS: 567.2(M + H).2-(2,4-Difluorophenyl)-N-(4-(2-(1-ethyl-1H-imidazol-4-yl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenylcarbamothioyl)acetamide 364 273

¹H NMR(400 MHz, DMSO-d₆) δ (ppm): 12.48(s, 1H), 11.83(s, 1H), 8.46(d,J=5.3 Hz, 1H), 8.02(d, J=12.1 Hz, 1H), 7.96(s, 1H), 7.79(s, 1H), 7.69(s,1H), 7.53–7.50(m, 2H), 7.38(t, J=6.5 Hz, 2H), 7.18(t, J=8.6 Hz, 2H),6.58(d, J=5.5Hz, 1H), 4.06(q, J= 7.2 Hz, 2H), 3.83(s, 2H), 1.40(t, J=7.2Hz, 3H). N-(4-(2-(1-ethyl-1H-imidazol-4-yl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenylcarbamothioyl)-2-(4-fluorophenyl)acetamide 365 274

¹H NMR(400 MHz, DMSO-d₆) δ (ppm): 12.54(s, 1H), 11.85(s, 1H), 8.56(d,J=5.7 Hz, 1H), 8.13–8.07(m, 3H), 7.78(s, 1H), 7.58–7.54(m, 2H),7.27–7.17(m, 4H), 6.75 (d, J=5.5 Hz, 1H), 4.10(q, J=7.2 Hz, 2H), 3.89(s,2H), 2.29(s, 3H), 1.42(t, J=7.2 Hz, 3H).N-(4-(2-(1-ethyl-1H-imidazol-4-yl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenylcarbamothioyl)-2- o-tolylacetamide 366275

¹H NMR(400 MHz, DMSO-d₆) δ (ppm): 12.46(s, 1H), 11.86(s, 1H), 8.46(d,J=5.5 Hz, 1H), 8.02(dd, J=2.1, 12.2 Hz, 1H), 7.96 (s, 1H), 7.80(d, J=0.8Hz, 1H), 7.69(s, 1H), 7.53–7.52(m, 2H), 7.47(d, J=8.0 Hz, 2H), 7.36(d,J=8.0 Hz, 2H), 6.58(d, J=5.5 Hz, 1H), 4.19(s, 1H), 4.06(q, J=7.2 Hz,2H), 3.87(s, 2H), 1.40(t, J=7.2 Hz, 3H).N-(4-(2-(1-ethyl-1H-imidazol-4-yl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenylcarbamothioyl)-2-(4-ethynylphenyl)acetamide 367 276

¹H NMR(400 MHz, DMSO-d₆) δ (ppm): 12.45(s, 1H), 11.85(s, 1H), 8.46(d,J=5.6 Hz, 1H), 8.03(d, J=12.0 Hz, 1H), 7.96(s, 1H), 7.79(s, 1H), 7.68(s,1H), 7.60–7.48(m, 2H), 7.44–7.36(m, 1H),. 7.24–7.09(m, 3H), 6.58(d,J=5.6 Hz, 1H), 4.06(q, J=7.2 Hz, 2H), 3.87(s, 2H), 1.40(t, J=7.2 Hz,3H). N-(4-(2-(1-ethyl-1H-imidazol-4-yl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenylcarbamothioyl)-2-(3-fluorophenyl)acetamide 368 277

¹H NMR(400 MHz, DMSO-d₆) δ (ppm): 12.50(s, 1H), 11.90(s, 1H), 8.45(d, J=5.6 Hz, 1H), 8.07(dd,J=2.4, 12.0 Hz, 1H), 7.96(d, J=1.2 Hz, 1H), 7.79(d,J=1.2 Hz, 1H), 7.68(s, 1H), 7.59–7.48(m, 3H), 7.42–7.3 8(m, 2H),7.35–7.18(m, 1H), 6.58 (d, J=5.6 Hz, 1H), 4.45(s, 1H), 4.06(q, J= 7.2Hz, 2H), 4.05(s, 2H), 1.40(t, J=7.2 Hz, 3H).N-(4-(2-(1-ethyl-1H-imidazol-4-yl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenylcarbamothioyl)-2-(2-ethynylphenyl)acetamide 369 278

¹H NMR(400 MHz, DMSO-d₆) δ (ppm): 8.45(d, J=5.6 Hz, 1H), 8.06 (dd,J=2.4, 12.8 Hz, 1H), 7.96(d, J=1.2 Hz, 1H), 7.79(d, J=1.2 Hz, 1H), 7.68(s, 1H), 7.56–7.48(m, 2H), 7.15(dd, J=1.6, 6.0 Hz, 1H), 7.09(td, J=1.2,8.0 Hz, 1H), 6.80(d, J=8.0 Hz, 1H), 6.76(t, J=8.0 Hz, 1H) 6.58(d, J=5.6Hz, 1H), 4.06 (q, J=7.2 Hz, 2H), 3.76(s, 2H), 1.40(t, J=7.2 Hz, 3H).LCMS: 518.1(M + H). N-(4-(2-(1-ethyl-1H-imidazol-4-yl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenylcarbamothioyl)-2-(2-hydroxyphenyl)acetamide 370 279

¹H NMR(400 MHz, DMSO-d₆) δ (ppm): 12.56(s, 1H), 11.74 (s, 1H), 8.54(d,J=5.69 Hz, 1H), 8.06(dd, J=2.4, 13.2 Hz, 1H), 7.94(d, J=1.2 Hz, 1H),7.74(s, 1H), 7.60–7.52 (m, 2H), 7.40(d, J=1.2 Hz, 1H), 7.31–7.25(m, 1H),7.23 (dd, J=1.6, 7.6 Hz, 1H), 7.00(d, J=7.6 Hz, 1H), 6.92 (td, J=1.2,7.6 Hz, 1H) 6.67(d, J=5.6 Hz, 1H), 4.29 (q, J=7.2 Hz, 2H), 3.81(s, H),3.78(s, 3H), 1.34(t, J= 7.2 Hz, 3H). LCMS: 561.1 (M + H).N-(4-(2-(1-ethyl-1H-imidazol-5-yl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenylcarbamothioyl)-2-(2-methoxyphenyl)acetamide 371 280

¹H NMR(400 MHz, DMSO-d₆) δ (ppm): 12.5(s, 1H), 11.78(s, 1H), 8.53(d, d,1H, J= 5.5 Hz), 8.01(d, 1H, J=12.7 Hz), 7.89(s, 1H), 7.52(m, 2H),7.3–7.41(m, 5H), 7.27(m, 1H), 7.03(d, 1H, J=1.0 Hz), 6.67(d, 1H, J= 5.5Hz), 4.09(q, 1H, J=7.1 Hz), 3.97(s, 3H), 1.42(d, 3H, J=7.0 Hz).LCMS:(M + H) 532.0 N-(3-fluoro-4-(2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylpropanamide 372 281

¹H NMR(400 MHz, DMSO-d₆) δ (ppm): 12.47(s, 1H), 11.82(s, 1H), 8.59(d,J=5.48 Hz, 1H), 8.02(m, 1H), 7.94(s, 1H), 7.51(m, 2H), 7.34(m, 5H),6.67(m, 1H), 3.94(s, 3H), 2.30(s, 3H). LCMS: 509.0(M + H)(E)-N-(3-Fluoro-4-(2-(1- (methoxyiinino)ethyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbainothioyl)-2-phenylacetainide 373 282

¹H NMR(400 MHz, DMSO-d₆) δ (ppm): 12.52(s,1H); 11.77(s, 1H); 8.50(d,J=5.1, 1H); 7.87(s, 1H); 7.82(d, J=8.6, 2H); 7.60 (d, J=8.6, 2H);7.39(s, 1H); 7.33–7.24(m, 5H); 7.03(s, 1H); 6.87(d, J=5.1, 1H); (s, 3H);3.80(s, 2H). LCMS:(M + H) 516.0N-(4-(2-(1-Methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-ylthio)phenylcarbamothioyl)-2- phenylacetamide 374 283

¹H NMR(400 MHz, CD₃OD) δ (ppm): 8.52 (d, J=5.5 Hz, 1H), 8.36(bs, 1H),8.04(dd, J=2.2, 12.1 Hz, 1H), 7.88–7.98(bm, 1H), 7.42(m, 1H),7.33–7.38(m, 3 H), 7.03–7.07 6.73(dd, J=0.8, 5.5 Hz H), 3.88– 4.40(3 bs,3H), 3.58–3.82(2bs, 4H), 2.68– 2.84(2 bs, 6H), 2.36–2.56(bs, 1H), 2.08–2.36(2bs, 1H). (S)-N-(4-(2-(3-(dimethylamino)pyrrolidine-1-carbonyl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenylcarbamothioyl)-2-(4- fluorophenyl)acetamide 375 284

LCMS: 591.1(M + H). N-(4-(2-(1-(2-Amino-2-oxoethyl)-1H-imidazol-4-yl)thieno[3,2-b]pyridin-7-yloxy)-3- fluorophenylcarbamothioyl)-2-(2-methoxyphenyl)acetamide

3-Fluoro-4-(2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)thieno[3,2-b]pyridin-7-yloxy)aniline(376) Step 1: 1-Methyl-1,2,3,6-tetrahydropyridin-4-yltrifluoromethanesulfonate (377)

LDA (1.5 N in THF, 8.1 mL, 12.17 mmol) was added to a solution of1-methylpiperidin-4-one (1.4 mL, 12.17 mmol) in THF (16 mL) at −78° C.,the mixture was allowed to warm to room temperature and stirred for 30min. The solution was cooled again to −78° C. and PhNTf₂ (5 g, 18.12mmol) was added in one portion; the reaction mixture was allowed to warmto room temperature and stirred for 3 h, poured into water, extractedwith ether, the extract was dried over anhydrous Na₂SO₄ and concentratedunder reduced pressure. The residue was purified by flash chromatography(EtOAc/Hexanes 1:5) affording 377 (2.38 g, 80% yield) as orange oil.LCMS:(M+H) 245.9.

Step 2:7-(2-Fluoro-4-nitrophenoxy)-2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)thieno[3,2-b]pyridine(379)

To a mixture of the triflate 377 (450 mg, 1.84 mmol),bis(pinacolato)diboron (477 mg, 2.02 mmol) and K₂CO₃ (541 mg, 5.52 mmol)in DME (3.7 mg), Pd(PPh₃)₄ (106 mg, 0.092 mmol) was added in one portionand the system was heated to reflux for 2 h under N₂. The reactionmixture was cooled and filtered. To the filtrate containing theintermediate 378 were added bromide 42 (435 mg, 1.84 mmol, scheme 8),CsF (838 mg, 5.52 mmol), NaHCO₃ (463 mg, 5.52 mmol) and water (0.8 mL),and the mixture was heated to reflux for additional 2 h. It was thendiluted with water and extracted with DCM; the organic solution wasextracted with 1N HCl, the aqueous phase was basified to pH˜11 byaddition of 2N aqueous NaOH, extracted with DCM; the extract was driedover anhydrous Na₂SO₄ and concentrated under reduced pressure affording379 (279 mg, 39% yield) as a brown solid. LCMS:(M+H) 385.9.

Step 3:3-Fluoro-4-(2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)thieno[3,2-b]pyridin-7-yloxy)aniline(376)

To a mixture of nitro compound 379 (279 mg, 0.72 mmol) and NH₄Cl (33 mg,0.612 mmol) in EtOH (7.2 mL)/water (3.6 mL) at 100° C. Fe powder (342mg, 6.2 mmol) was added in one portion and the mixture was heated toreflux with vigorous stirring for 40 min. The mixture was filteredthrough Celite®, the Celite® washed with EtOH and the combined filtrateswere concentrated under reduced pressure. The residue was dissolved inMeOH and purified by flash chromatography (DCM/MeOH 5:1) providing 376(171.3 mg, 0.48 mmol, 67% yield) as a yellow solid. LCMS:(M+H) 356.0.

TABLE 25 Compounds 380–384(examples 285–289) prepared from the amine376(scheme 80) Cpd Ex. Sctructure Characterization 380 285

¹H NMR(400 MHz, DMSO-d₆) δ (ppm): 12.64(s, 1H), 11.84(s, 1H), 8.49(d,J=5.4Hz, 1H), 8.0(dd, J=11.2, 2Hz, 1H), 7.53(m, 3H), 7.38(m, 2H),7.18(m, 2H), 6.64(d, J=5.4 Hz, 1H), 6.39(s, 1H), 3.83(s, 2H), 3.3(m,2H), 2.83(m, 2H), 2.69(m, 2H), 2.46(s, 3H). LCMS:(M + H) 551.1N-(3-fluoro-4-(2-(1-methyl-1,2,3,6 tetrahydropyridin-4-yl)thieno[3,2-b]pyridin-7 yloxy)phenylcarbamothioyl)-2-(4-fluorophenyl)acetamide 381 286

¹H NMR(400 MHz, DMSO-d₆) δ (ppm): 12.5 (s, 1H), 11.84(s, 1H), 8.48(1H,J=5.5 Hz, 1H), 8.03(dd, J=1.8, 12.1 Hz, 1H), 7.56–7.51 (m, 3H), 7.37(m,1H), 7.21–7.15(m, 3H), 6.63 (d, J=5.5 Hz, 1H), 6.38(t, J=3 Hz, 1H), 3.88(s, 2H), 3.14(m, 2H), 2.66(m, 4H), 2.35(s, 3H), 2.9(s, 3H). LCMS:(M + H)547.2 N-(3-fluoro-4-(2-(1-methyl-1,2,3,6-tetrahydropyri-din-4-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-o-tolylacetamide 382 287

¹H NMR(400 MHz, DMSO-d₆) δ (ppm): 12.46(s, 1H), 11.91(s, 1H), 8.49(d,J=5.3 Hz, 1H), 8.15(s, 1H), 8.04(dd, J=12.1, 1.8 Hz, 1H), 7.56–7.49(m,3H), 7.44(m, 1H), 7.36 (m, 1H), 7.27(m, 1H), 6.64(d, J=5.3 Hz, 1H),6.39(s, 1H), 4.59(s, 1H), 4.04(s, 2H), 3.32(m, 2H), 2.85(m, 2H), 2.70(m,2H), 2.47 (s, 3H). LCMS: 575.22-(2-ethynyl-4-fluorophenyl)-N-(3-fluoro-4-(2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)acetamide 383 288

¹H NMR(400MHz, DMSO-d₆) δ (ppm): 12.47 (s, 1H), 11.82(s, 1H), 8.45(d,1H, J=5.5 Hz), 7.98(dd, 1H, J=1.3, 13.3 Hz), 7.50–7.48(m, 3H),7.33–7.31(m, 4H), 7.28–7.26(m, 1H), 6.60(d, 1H, J=5.3Hz), 6.36(t, 1H,J=3.3 Hz), 3.80(s, 2H), 3.07(s, 2H), 2.60(s, 4H), 2.29(s, 3H). LCMS:533.1(M + H). N-(3-fluoro-4-(2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide 384 289

¹H NMR(400 MHz, DMSO-d₆) δ (ppm): 12.42(s, 1H), 11.83(s, 1H), 8.41(d,J=5.3 Hz, 1H), 7.97(dd, J=2.1, 12.1 Hz, 1H), 7.49– 7.42(m, 4H),7.34–7.32(m, 2H), 7.27–7.24 (m, 1H), 6.58(d, 1H,J=5.5 Hz), 6.32(t, 1H,J=3.3 Hz),4.38(s, 1H), 3.98(s, 2H), 3.15(s, br, 2H), 2.69(s, br, 2H,2.60(s, br, 2H), 3.39 (s, 3H). LCMS:(M + H) 557.12-(2-Ethynylphenyl)-N-(3-fluoro-4-(2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)acetamide

Example 290N-(4-(2-(1-Acetyl-1,2,3,6-tetrahydropyridin-4-yl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenylcarbamothioyl)-2-phenylacetamide(385) Step 1: tert-Butyl4-(trifluoromethylsulfonyloxy)-5,6-dihydropyridine-1(2H)-carboxylate(386)

LDA (1.5 N in THF, 7.2 mL, 10.68 mmol) was added to a solution oftert-butyl 4-oxopiperidine-1-carboxylate (1.94 mL, 9.74 mmol) in THF (13mL) at −78° C., the mixture was allowed to warm to room temperature andstirred for 30 min. The solution was cooled to −78° C. and1,1,1-trifluoro-N-(pyridin-2-yl)-N-(trifluoromethylsulfonyl)methanesulfonamide (4 g, 11.2 mmol) was added in one portion. Thereaction mixture was warmed to room temperature and stirred for anadditional hour, diluted with EtOAc, washed with 1N HCl, water, brineand concentrated under reduced pressure to a minimum volume. The whiteprecipitate thus formed was removed by filtration, the filtrate wasconcentrated and the residue was distilled under reduced pressureaffording 386 (2.80 g, 86% yield) as brown liquid. LCMS:(M−Boc+H) 232.1(26%).

Steps 2-3: tert-Butyl4-(7-(2-fluoro-4-nitrophenoxy)thieno[3,2-b]pyridin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate(388)

Following the procedure described above for compound 379 (scheme 80) butreplacing triflate 377 with triflate 386 the title compound 388 wasobtained in 56% yield. LCMS: (M+H) 472.5 (via the intermediate boronate387 which was not isolated from the reaction mixture).

Step 4:7-(2-Fluoro-4-nitrophenoxy)-2-(1,2,3,6-tetrahydropyridin-4-yl)thieno[3,2-b]pyridine(389)

To a solution of the carboxylate 388 (1 g, 2.13 mmol) in DCM (4.3 mL)TFA (4.3 mL) was added and the reaction mixture was stirred 2 h at roomtemperature. The solvent was removed under reduced pressure, the residuewas suspended in aqueous sodium bicarbonate, the mixture was extractedwith DCM, EtOAc and DCM; the combined extracts were filtered and therecovered solids were collected and dried. The filtrate was dried overanhydrous Na₂SO₄, concentrated under reduced pressure and the residuewas combined with the solid material obtained upon filtration, to afford389 (806 mg, 100% yield) as a yellow solid. LCMS:(M+H) 372.1.

Step5:1-(4-(7-(2-Fluoro-4-nitrophenoxy)benzo[b]thiophen-2-yl)-5,6-dihydropyridin-1(2H)-yl)ethanone(390)

To a suspension of the nitro amine 389 (400 mg, 1.08 mmol) and DIPEA(0.207 mL, 1.19 mmol) in DCM acetyl chloride (0. 15 mL, 2.16 mmol) wasadded at room temperature and the mixture was stirred for 1 h. It wasthen concentrated under reduced pressure and the residue was purified byflash chromatography (eluent 5% MeOH to 10% MeOH in DCM) affording 390(358.2 mg, 80% yield) as a white solid. LCMS: (M+H) 414.4.

Step6:1-(4-(7-(4-Amino-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)-5,6-dihydropyridin-1(2H)-yl)ethanone(391)

To a mixture of the nitro compound 390 (358.2 mg, 0.87 mmol) and NH₄Cl(39.4 mg, 0.74 mmol) in EtOH (8.7 mL)/water (4.3 mL) at 100° C. Fepowder (411.3 mg, 7.36 mmol) was added in one portion and the mixturewas heated to reflux under vigorous stirring for 40 min. It was thenfiltered through Celite®, the Celite® was washed with EtOH and thecombined filtrates were concentrated under reduced pressure. The residuewas dissolved in DCM, washed with water, dried (anhydrous Na₂SO₄) andconcentrated under reduced pressure affording 391 (256.5 mg, 77% yield)as a white solid. LCMS:(M+H) 384.2.

Step 7:N-(4-(2-(1-Acetyl-1,2,3,6-tetrahydropyridin-4-yl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenylcarbamothioyl)-2-phenylacetamide(385)

Starting from compound 391 and following the procedure described forcompound 31b (Scheme 5, step 4, example 28); title compound 385 wasobtained in 70% yield. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.45 (s, 1H),11.83 (s, 1H), 8.49 (dd, J=5.5 Hz, J=0.8 Hz, 1H), 8.00 (d, J=11.9 Hz,1H), 7.58-7.49 (m, 3H), 7.41-7.35 (m, 2H), 7.21-7.13 (m, 2H), 6.65 (dd,J=5.5, 1 Hz, 1H), 6.50 (m, 1H), 4.2 (m, 1H), 4.15 (m, 1H), 3.83 (s, 2H),3.70-3.67 (m, 2H), 2.68 (m, 1H), 2.59 (m, 1H), 2.09 (s, 1.5H), 2.04 (s,1.5H). LCMS: 579.2 (M+H).

TABLE 26 Compounds 392–405(examples 291–304) prepared according to theprocedures similar to ones shown in the schemes 10, 11, 13–15, 19 CpdEx. Structure Characterization 392 291

¹H NMR(400 MHz, DMSO-d₆) δ (ppm):&12.46(s, 1H); 11.83(s, 1H); 8.52(d,J=&5.5 Hz, 1H); 8.02(s, 1H); 8.02–7.99(m,&1H); 7.83(s, 1H); 7.77–7.74(m,1H);&7.56–7.51(m, 2H); 7.44(t, J=7.6 Hz,&1H); 7.39–7.34(m, 3H),7.19–7.14(m,&2H); 6.66(d, J=5.5 Hz, 2H); 3.82(s,&2H); 3.72(s, 2H);3.41(t, J=5.9 Hz,&4H); 3.20(s, 6H); 2.66(t, J=5.9 Hz,&4H). LCMS:(M + H)677.3 N-(4-(2-(3-((Bis(2- methoxyethyl)amino)methyl)phenyl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenylcarbamothioyl)-2-(4-fluorophenyl)acetamide 393 292

¹H NMR(400 MHz, DMSO-d₆) δ (ppm):&12.46(s, 1H); 11.83(s, 1H); 8.52(d,J=&5.5 Hz, 1H); 8.03(s, 1H); 8.00(d. J=11.5&Hz, 1H); 7.84(d, J=8.2 Hz,2H); 7.55–&7.51(m, 2H); 7.42–7.35(m, 4H); 7.20–&7.15(m, 2H); 6.65(d,J=5.3 Hz, 1H);&3.82(s, 2H); 3.50(s, 2H); 2.46–2.20(m,&8H); 2.14(s, 3H).LCMS:(M + H) 644.2 N-(3-Fluoro-4-(2-(4-((4-methylpiperazin-1-&yl)methyl)phenyl)thieno[3,2-b]pyridin-7-&yloxy)phenylcarbamothioyl)-2-(4- fluorophenyl)acetamide 394 283

¹H NMR(400 MHz, DMSO-d₆) δ (ppm):&12.48(s, 1H), 11.86(s, 1H), 8.53(d,J=&5.3 Hz, 1H), 8.03(m, 3H), 7.86(m, 2H),&7.47(m, 9H), 6.65(d, J=5.28Hz, 1H),&4.1(s, 1H), 3.86(s, 2H), 3.70(s, 2H),&3.56(s, 2H), 3.83(s, 2H),3.33(s, 2H),&2.29(s, 3H). LCMS: 625.2(M + H).2-(4-ethynylphenyl)-N-(3-fluoro-4-(2-(4-(((2-hydroxyethyl)(methyl)amino)methyl)phenyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)acetamide 395 294

¹H NMR(400 MHz, DMSO-d₆) δ (ppm):12.46(s, 1H), 11.83(s, 1H), 8.86(s,2H),&8.54(d, J=5.28 Hz, 1H), 8.13(s, 1H),&8.03(m, 3H), 7.98(d, J=8.0 Hz,2H),&7.62(d, J=8.0 Hz, 2H), 7.53(m, 9H),&7.35(m, 2H), 7.16(t, J=9 Hz,1H), 6.68&(d, J=5.3 Hz, 1H), 4.2(s, 2H), 3.81(s,&2H), 3.70(s, 2H),3.56(s, 2H), 3.83(s,&2H), 2.89(m, 2H), 1.61(m, 2H), 0.9(t, J=&7.24 Hz,3H). LCMS: 603.2(M + H). N-(3-fluoro-4-(2-(4-((propylamino)methyl)phenyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-(4- fluorophenyl)acetamide 396 295

¹H NMR(400 MHz, DMSO-d₆) δ (ppm):&12.46(s, 1H), 11.83(s, 1H), 8.54(d,J=&5.1 Hz, 1H), 8.15(s, 1H), 7.99(m, 3H),&7.68(m, 1H), 7.55(d, J=8.8 Hz,2H),&7.35(m, 2H), 7.11(m, 2H) 6.67(d, J=&5.1 Hz, 1H), 4.38(m, 1H),3.82(s, 3H),&1.25(m, 3H). LCMS: 647.3(M + H). N-(4-(2-(4-((ethyl(2-methoxyethyl)amino)methyl)phenyl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenylcarbamothioyl)-2-(4-fluorophenyl)acetamide 397 296

¹H NMR(400 MHz, DMSO-d₆) δ (ppm):&12.50(s, 1H), 11.85(s, 1H), 8.50(d,J=&5.3 Hz, 1H), 8.20(m, 1H), 8.18(s, 1H),&8.04(s, 1H), 7.83(d, J=8.4 Hz,1H),&7.53(m, 1H), 7.29(m, 6H), 6.62(d, J=&5.3 Hz, 1H), 3.81(s, 2H),3.52(s, 1H),&2.31(m, 15H), 2.16(s, 3H), 2.15(s, 3H).&LCMS: 683.1(M + H).N-(3-fluoro-4-(2-(4-((methyl(2-(4-methylpiperazin-1-yl)ethyl)amino)methyl)phenyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide 398 297

¹H NMR(400 MHz, DMSO-d₆) δ (ppm):&12.47(s, 1H), 11.84(s, 1H), 8.53(d,J=&5.5 Hz, 1H), 8.19(s, 1H), 8.13(s, 1H),&8.01(d, J=12.1 Hz, 1H),7.84(d, J=&11.7Hz, 1H), 7.73(d, J=8.0 Hz, 1H),&7.62(t, J=7.8 Hz, 2H),7.52(m, 2H),&7.37(m, 2H), 7.17(t, J=8.8 Hz, 2H),&6.67(d, J=5.5 Hz, 1H),3.93(s, 2H),&3.62(t, J=5.9 Hz, 2H), 2.76(m, 2H),&2.43(s, 3H). LCMS:637.2(M + H). N-(3-fluoro-4-(2-(2-fluoro-4-((2-methoxyethylamino)methyl)phenyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-(4- fluorophenyl)acetamide 399298

¹H NMR(400 MHz, DMSO-d₆) δ (ppm):&12.42(s, 1H), 11.84(s, 1H), 8.51(d,J=&5.5 Hz, 1H), 8.16(s, 1H), 8.03(s, 1H),&8.00(dd, J=1.9, 13.3 Hz, 1H),7.84(dd,&J=1.8, 6.5 Hz, 2H), 7.53–7.52(m 2H),&7.46(d, J=8.2 Hz, 2H),7.38–7.34(m,&2H), 7.19–7.16(m, 2H), 6.64(dd, J=1.0,&6.5 Hz, 1H), 3.82(s,2H), 3.8 0(s, 2H),&3.41(t, J=5.7 Hz, 2H), 3.23(s, 3H),&2.70(t, 2H, J=5.7Hz). LCMS:(M + H)&619.1 N-(3-fluoro-4-(2-(4-((2-methoxyethylamino)methyl)phenyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-(4-fluorophenyl)acetamide 400 299

¹H NMR(400 MHz, DMSO-d₆) δ (ppm):&11.05(s, 1H), 10.61(s, 1H),8.93(m,&2H), 8.52(d, J=5.5 Hz, 1H), 8.12(s,&1H), 7.97(d, J=8.4 Hz, 2H),7.82(dd, J=&2.4, 12.9 Hz, 2H), 7.62(d, J=8.2 Hz,&1H), 7.49–7.41(m, 2H),7.36–7.33(m,&2H), 7.18–7.16(m, 2H), 6.64(dd, J=0.8,&5.3 Hz, 1H).LCMS:(M + H)603.2. N-(3-fluoro-4-(2-(4-((2- methoxyethylamino) methyl)phenyl) thieno [3,2- bipyridin-7- yloxy)phenylcarbamoyl)-2-(4-fluorophenyl) acetamide 401 300

¹H NMR(400 MHz, DMSO-d₆) δ (ppm):&12.48(s, 1H), 11.85(s, 1H), 8.59(d,J=&5.2 Hz, 1H), 8.31(s, 1H), 8.19(d, J=8.4&Hz, 2H), 8.04(d, J=8.4 Hz,2H), 8.07–&8.00(m, 1H), 7.61–7.53(m, 2H), 7.38&(dd, J=8.8, 5.6 Hz, 2H),7.19(tt, J=8.8,&2.0 Hz, 2H), 6.73(d, J=5.2 Hz, 1H),&3.84(s, 2H), 3.29(s,3H). LCMS:(M + H)&610.1. N-(3-fluoro-4-(2-(4-(methylsulfonyl)phenyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-(4- fluorophenyl)acetamide 402 301

¹H NMR(400 MHz, DMSO-d₆) δ (ppm):&12.47(s, 1H), 11.83(s, 1H), 8.56(d,J=&5.6 Hz, 1H), 8.16(s, 1H), 8.03(d, J=&12.4 Hz, 1H), 7.96(d, J=8.0 Hz,2H),&7.61–7.49(m, 4H), 7.38(dd, J=8.4, 5.6&Hz, 2H), 7.19(t, J=9.2 Hz,2H), 6.69(d,&J=5.6 Hz, 1H), 3.84(s, 2H), 3.01(s,&3H), 2.96(s, 3H).LCMS:(M + H) 603.2 4-(7-(2-fluoro-4-(3-(2-(4-fluorophenyl)acetyl)thioureido)phenoxy)thieno[3,2-b]pyridin-2-yl)-N,N-dimethylbenzamide 403 302

¹H NMR(400 MHz, CD₃CN) δ (ppm):&8.51(d, J=5.5Hz, 1H), 7.99(dd, J=& 2.5,12.3 Hz, 1H), 7.84(s, 1H), 7.82(d,&J=8.2 Hz, 2H), 7.32–7.53(m,9H),&6.62(d, J=4.5 Hz, 1H), 3.81(s, 2H),&3.54(s, 2 H), 2.30–2.53(bs,8H), 2.22&(s, 3 H). N-(3-fluoro-4-(2-(4-((4-methylpiperazin-1-yl)methyl)phenyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide 404 303

¹H NMR(400 MHz, DMSO-d₆) δ (ppm):&12.43(s, 1H), 11.84(s, 1H), 8.51(d,J=&5.5 Hz, 1H), 7.98–8.03(m, 2H), 7.83&(dd, J=1.8, 6.5 Hz, 2H), 7.54(m,2H),&7.44–7.47(m, 2H), 7.41(d, J=8.4 Hz,&2H), 7.34(dd, J=2.0, 6.5 Hz,2H), 6.64&(m, 1H), 4.17(s, 1H), 3.85(s, 2H), 3.49&(s, 2H), 2.37(bs, 6H),2.17(s, 3H). (A&signal corresponding to 2H is hidden by&the residualDMSO signal). 2-(4-ethynylphenyl)-N-(3-fluoro-4-(2-(4-((4-methylpiperazin-1-yl)methyl)phenyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)acetamide 405 304

¹H NMR(400 MHz, DMSO-d₆) δ (ppm):&12.45(s, 1H), 11.90(s, 1H), 8.52(d,J=&5.5 Hz, 1H), 8.04(m, 2H), 7.85(d, J=&8.2 Hz, 2H), 7.54(m, 2H),7.43(m, 3H),&7.36(dd, J=2.8, 9.3 Hz, 1H), 7.26(m,&1H), 6.65(dd, J=0.8,5.3 Hz, 1H), 4.58&(s, 1H), 4.03(s, 2H), 3.53(s, 2H), 2.31&(bs, 3H), (Apart of the NMR spectrum is&hidden by the residual DMSO signal).2-(2-ethynyl-4-fluorophenyl)-N-(3-fluoro-4-(2-(4-((4-methylpiperazin-1-yl)methyl)phenyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)acetamide

Example 304N-(4-(2-Ethynylthieno[3,2-b]pyridin-7-yloxy)-3-fluorophenylcarbamothioyl)-2-phenylacetamide(406) Step 1: 7-(2-Fluoro-4-nitrophenoxy)-2-iodothieno[3,2-b]pyridine(408)

A mixture of the chloride 407 (Ragan J. A. et al, Organic ProcessResearch and Development 2003, 7, 676-683) (7.0 g, 23.7 mmol), thephenol (11.15 g, 3 eq, 71.1 mmol), K₂CO₃ (13.08 g, 4 eq, 94.8 mmol) inPh₂O (30 ml) was heated to 200° C. for 3 hrs. The reaction mixture wascooled to RT, diluted with DCM, filtered and then concentrated. Theresultant solid was triturated with diethyl ether, collected byfiltration to afford 408 (7.3 g, 74% yield) which was used directly inthe next step with no additional purification. LCMS: 417.0 (M+H).

Step 2:7-(2-Fluoro-4-nitrophenoxy)-2-((trimethylsilyl)ethynyl)thieno[3,2-b]pyridine(409)

To a solution of the iodide 408 (4.5 g, 10.8 mmol) in dry THF (120 ml)at was added CuI (205 mg, 0.1 eq, 1.08 mmol), TEA (2.73 g, 2.5 eq, 27mmol), ethynyltrimethylsilane (2.12 g, 2 eq, 21.6 mmol) and Pd(PPh₃)₂Cl₂(212 mg, 0.028 eq, 0.30 mmol) and the reaction mixture was heated toreflux for 2 hours. It was then cooled to RT and partitioned betweenEtOAc and water. The organic phase was collected, dried over anhydroussodium sulfate, filtered and adsorbed onto silica gel. Purification bycolumn chromatography (30% EtOAc/hexane) afforded 409 (2.2 g, 53%yield). LCMS: 387.1 (M+H).

Step 3: 2-Ethynyl-7-(2-fluoro-4-nitrophenoxy)thieno[3,2-b]pyridine (410)

To a solution of the alkyne 409 (2.2 g, 5.69 mmol) in THF (30 ml) wasadded a solution of TBAF (8.53 mL, 1.5 eq, 1M soln in THF) in HOAc (30ml), and the reaction mixture was stirred at RT overnight. It was thenconcentrated to dryness and partitioned between water and EtOAc. Theorganic phase was washed well with satd. NaHCO₃ soln, collected, driedover anhydrous Na₂SO₄, filtered and concentrated. The crude mixture wasadsorbed onto silica gel then purified by column chromatography (30%EtOAc in hexane) to afford 410 (1.4 g, 72% yield). LCMS: 415.2 (M+H).

Steps 4-5:N-(4-(2-Ethynylthieno[3,2-b]pyridin-7-yloxy)-3-fluorophenylcarbamothioyl)-2-phenylacetamide(406)

To a solution of the alkyne 410 (200 mg, 0.64 mmol) in MeOH (10 ml) wasadded SnCl₂×2H₂O (574 mg, 4 eq, 2.54 mmol) and the reaction mixture washeated to reflux for 3 hours. It was then cooled to RT, concentrated andcrude amine 411 was used directly in the next step with no additionalpurification (182 mg, 100%). To a solution of 411 (182 mg, 0.64 mmol) inEtOH (2 ml) and toluene (6 ml) was added 2-phenylacetyl isothiocyanate(227 mg, 2 eq, 1.28 mmol) and the reaction mixture was stirred at RT for2 hrs, concentrated under reduced pressure and the residue was purifiedby column chromatography (1:3 EtOAc:hexane) to afford 406 as a whitesolid (25 mg, 9% yield). ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.49 (s,1H), 11.82 (s, 1H), 8.58 (d, J=5.48 Hz, 1H), 8.01 (m, 1H), 7.88 (s, 1H),7.50 (m, 2H), 7.25 (m, 5H), 6.73 (d, J=5.48 Hz, 1H), 5.01 (s, 1H), 3.81(s, 2H). LCMS: 462.2 (M+H).

Example 305N-(4-(2-(1-Ethyl-1H-1,2,3-triazol-4-yl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenylcarbamothioyl)-2-phenylacetamide(412) Step 1:2-(1-Ethyl-1H-1,2,3-triazol-4-yl)-7-(2-fluoro-4-nitrophenoxy)thieno[3,2-b]pyridine(413)

To a solution of NaN₃ (107.3 mg, 1.65 mmol) in DMSO (5 ml) was addedethyl iodide (257 mg, 1.65 mmol) and the reaction mixture was stirredfor 12 hrs at RT. The alkyne 410 (520 mg, 1.65 mmol) and Cu(OAc)₂×H₂O(66 mg, 0.2 eq, 0.331 mmol) were added and the deep red reaction mixturewas allowed to stir at RT overnight. After 72 hrs, an orange precipitatehad formed. The mixture was diluted with water and the solid wascollected by filtration. The orange solid 413 was used directly in thenext step with no additional purification (620 mg, 97% yield). LCMS:386.2 (M+H).

Steps 2-3:N-(4-(2-(1-Ethyl-1H-1,2,3-triazol-4-yl)thieno[3,2-b]pyridin-7-yloxy-3-fluorophenylcarbamothioyl)-2-phenylacetamide(412)

To a suspension of the nitro compound 413 (300 mg, 0.78 mmol) in MeOH(20 ml), THF (20 ml) and water (4 ml) was added zinc (456 mg, 9 eq, 7.01mmol.) followed by NH₄Cl (83 mg, 2 eq, 1.56 mmol) and the reactionmixture was heated to reflux for 4 hrs. The reaction mixture wasconcentrated to dryness and the resultant solid was triturated withdiethyl ether to afford the amine 414 as a white solid (mixture withZnCl₂) which was used crude in the next step (198 mg, 71% yield). To asuspension of the amine 414 (198 mg, 0.57 mmol) in EtOH (˜2 ml) andtoluene (˜6 ml) was added the 2-phenylacetyl isothiocyanate (197 mg, 2eq, 1.11 mmol) and the reaction mixture was stirred at RT for 3 hrs. Themixture was concentrated to dryness and the residue was purified bycolumn chromatography (EtOAc) to afford 412 as a pale yellow solid (115mg, 38% yield). ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.51 (s, 1H), 11.84(s, 1H), 8.84 (s, 1H), 8.51 (d, J=5.48 Hz, 1H), 8.03 (m, 1H), 7.91 (s,1H), 7.53 (m, 2H), 7.28 (m, 7H), 6.65 (d, J=5.48 Hz, 1H), 4.46 (q,J=7.24 Hz, 2H), 4.03 (q, J=7.24 Hz, 2H), 3.82 (s, 2H), 1.49 (t, J=7.43Hz, 3H). LCMS: 574.2 (M+H).

Example 306N-(3-Fluoro-4-(2-(1-methyl-1H-imidazol-4-yl)thieno[3,2-b]pyridin-7-ylamino)phenylcarbamothioyl)-2-phenylacetamide (415) Step 1. 2-Fluoro-4-nitroaniline(416)

A stirred solution of 3,4-difluoronitrobenzene (2.00 g, 12.57 mmol) inammonium hydroxide (20 ml, 28% in water) was heated at 150° C. in asealed flask for 3.5 hrs. It was then cooled to room temperature, andthe resulting suspension was diluted with water, shaken for 15 min. Theresultant precipitate was collected by filtration, rinsed with water,air-dried, and dried under high vacuum to afford title compound 416(1.76 g, 90% yield) as a yellow crystalline solid. LCMS: 157.0 (M+H)⁺and 179.0 (M+Na)⁺.

Step 2.N-(2-Fluoro-4-nitrophenyl)-2-(1-methyl-1H-imidazol-4-yl)thieno[3,2-b]pyridin-7-amine(417)

A suspension of 175 (500 mg, 2.00 mmol, scheme 35), 416 (406 mg, 2.60mmol), Pd₂(dba)₃ (73 mg, 0.08 mmol), (2-biphenyl)dicyclohexylphosphine(56 mg, 0.16 mmol), and K₃PO₄ (638 mg, 3.00 mmol) in toluene (20 ml) wasdegassed for 15 min with nitrogen, and then heated at 110° C. for 22 hrsin a sealed flask [ J. P. Wolfe, H. Tomori J. P. Sadighi J. Yin, S. L.Buchwald J. Org. Chem. 2000, 65, 1158-1174]. After cooling to roomtemperature the reaction mixture was filtered, the filtrate wasconcentrated and the residue was adsorbed on silica gel and subjected toflash column chromatography (eluents MeOH/CH₂Cl₂: 2/98 to 10/90).Fractions containing the product were combined, concentrated and treatedwith AcOEt/hexanes to afford title compound 417 (370 mg, 50% yield) as ayellow-orange solid. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 9.57 (bs, 1H),8.45 (d, J=5.1 Hz, 1H), 8.22 (dd, J=11.3, 2.5 Hz, 1H), 8.06 (dd, J=8.9,2.3 Hz, 1H), 7.83 (d, J=1.2 Hz, 1H), 7.70 (d, J=1.2 Hz, 1H), 7.63 (s,1H), 7.24 (t, J=8.7 Hz, 1H), 6.94 (bd, J=4.7 Hz, 1H), 3.71 (s, 3H).LCMS: 370.0 (M+H)⁺.

Step 3.2-Fluoro-N1-(2-(1-methyl-1H-imidazol-4-yl)thieno[3,2-b]pyridin-7-yl)benzene-1,4-diamine(418)

To a stirred suspension of nitro compound 417 (370 mg, 1.00 mmol) in amixture of MeOH (20 mL) and water (10 mL) were added iron powder (280mg, 5.01 mmol) and NH₄Cl (107 mg, 2.00 mmol). The reaction mixture washeated to reflux for 2 hrs, cooled to room temperature and filteredthrough celite. The filtrate was concentrated, diluted with minimalamount of methanol and treated with AcOEt/hexanes, to afford titlecompound 418 (463 mg, quantitative yield, ammonium salt) as a yellowsolid. LCMS: 340.0 (M+H)⁺.

Step 4.N-(3-Fluoro-4-(2-(1-methyl-1H-imidazol-4-yl)thieno[3,2-b]pyridin-7-ylamino)phenylcarbamothioyl)-2-phenylacetamide (415)

To a stirred solution of 418 (200 mg, 0.59 mmol) in a mixture ofanhydrous toluene/ethanol (15mL/15mL) was slowly added a solution of2-phenylacetyl isothiocyanate (522 mg, 2.95 mmol) in a mixture ofanhydrous toluene/ethanol (5mL/5mL). The reaction mixture was stirred atroom temperature for 4 hrs under nitrogen, concentrated, and adsorbed onsilica gel. The crude material was purified by flash columnchromatography (eluents 2% of NH₄OH in methanol/CH₂Cl₂ from 5/95 to10/90) followed by trituration with AcOEt (with traces ofacetone)/hexanes, to afford title compound 415 (183 mg, 60% yield) as apink solid. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.51 (s, 1H), 11.81 (s,1H), 8.82 (bs, 1H), 8.22 (d, J=5.5 Hz, 1H), 7.91 (dd, J=12.4, 2.3 Hz,1H), 7.79 (d, J=1.1 Hz, 1H), 7.69 (d, J=0.8 Hz, 1H), 7.53 (s, 1H), 7.44(dd, J=8.6, 2.2 Hz, 1H), 7.40-7.24 (m, 6H), 6.42 (dd, J=5.55, 2.22 Hz,1H), 3.83 (s, 2H), 3.71 (s, 3H). LCMS: 517.0 (M+H)⁺.

Example 307N-(3-Fluoro-4-(thieno[3,2-b]pyridin-7-ylamino)phenylcarbamothioyl)-2-phenylacetamide(419)

The title compound 419 (example 307) was obtained in three steps from 2and 416 as a beige solid following the same procedure as for the example306, steps 2-4 (scheme 84). ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.49 (s,1H), 11.81 (s, 1H), 8.81 (s, 1H), 8.28 (d, J=5.5 Hz, 1H), 7.98 (d, J=5.5Hz, 1H), 7.89 (dd, J=12.3, 2.2 Hz, 1H), 7.50-7.20 (m, 8H), 6.45 (dd,J=5.4, 2.3 Hz, 1H), 3.83 (s, 2H). LCMS: 437.0 (M+H)⁺.

Example 308N-(3-Fluoro-4-(methyl(2-(1-methyl-1H-imidazol-4-yl)thieno[3,2-b]pyridin-7-yl)amino)phenylcarbamothioyl)-2-phenylacetamide(324) Step 1.N-Methyl-2-(1-methyl-1H-imidazol-4-yl)thieno[3,2-b]pyridin-7-amine (421)

A stirred suspension of 175 (500 mg, 2 mmol) and methylaminehydrochloride (15 g, 222 mmol) in iso-propanol (50 ml) was heated at130° C. in a sealed flask for four days. It was then cooled to roomtemperature, poured in water, and the pH was adjusted to 10 with 1NNaOH. After extraction of the aqueous phase with AcOEt, the combinedorganic phase was concentrated and purified by flash columnchromatography (eluents 2% of NH₄OH in methanol/CH₂Cl₂: 10/90 to 40/60)to afford title compound 421 (487 mg, 99% yield, hydrate form) as abeige solid. LCMS: 245.0 (M+H)⁺.

Step 2.N-(2-Fluoro-4-nitrophenyl)-N-methyl-2-(1-methyl-1H-imidazol-4-yl)thieno[3,2-b]pyridin-7-amine(422)

A stirred suspension of 421 (500 mg, 2 mmol), 3,4-difluoronitrobenzene(795 mg, 5 mmol) and cesium carbonate (1.63 g, 5 mmol) in anhydrous DMF(50 ml) was heated at 85° C. under nitrogen for 7 hrs. It was thencooled down to room temperature poured in water, and extracted withdichloromethane. The combined organic extracts was concentrated andpurified twice by flash column chromatography (eluents 2% of NH₄OH inmethanol/CH₂Cl₂: 5/95 to 10/90) to afford title compound 422 (144 mg,19% yield) as a sticky yellow solid. LCMS: 384.0 (M+H)⁺.

Step 3.N-(3-Fluoro-4-(methyl(2-(1-methyl-1H-imidazol-4-yl)thieno[3,2-b]pyridin-7-yl)amino)phenylcarbamothioyl)-2-phenylacetamide(420)

The title compound 420 was obtained in two steps from 422 as a palebrown solid following the same procedure as in example 306, steps 3 and4 (scheme 84). ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.68 (s, 1H), 11.86(s, 1H), 8.37 (d, J=5.7 Hz, 1H), 8.05 (dd, J=12.6, 2.3 Hz, 1H), 7.64 (d,J=1.2 Hz, 1H), 7.58 (d, J=0.8 Hz, 1H), 7.53 (dd, J=8.7, 2.1 Hz, 1H),7.47-7.40 (m, 2H), 7.38-7.26 (m, 5H), 6.82 (d, J=5.7 Hz, 1H), 3.83 (s,2H), 3.64 (s, 3H), 3.38 (s, 3H). LCMS: 531.0 (M+H)⁺.

Example 309N-(3-Fluoro-4-(methyl(2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yl)amino)phenylcarbamothioyl)-2-phenylacetamide(423)

The title compound 423 was obtained in four steps from 214 (scheme 46)as a beige solid following the same procedure as in example 308, steps1-3 (scheme 85). ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.69 (s, 1H), 11.84(s, 1H), 8.45 (d, J=5.5 Hz, 1H), 8.07 (dd, J=12.6, 2.2 Hz, 1H), 7.65 (s,1H), 7.56 (dd, J=8.7, 2.2 Hz, 1H), 7.46 (t, J=8.8 Hz, 1H), 7.38-7.25 (m,6H), 6.92-6.87 (m, 2H), 3.87 (s, 3H), 3.83 (s, 2H), 3.39 (s, 3H). LCMS:531.0 (M+H)⁺.

Example 310N-(3-Fluoro-4-(methyl(thieno[3,2-b]pyridin-7-yl)amino)phenylcarbamothioyl)-2-phenylacetamide(424)

The title compound 424 was obtained in four steps from 2 as a beigesolid following the same procedure as in example 308, steps 1-3 (scheme85). ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.62 (s, 1H), 11.86 (s, 1H),8.43 (d, J=5.5 Hz, 1H), 7.99 (dd, J=12.5, 2.2 Hz, 1H), 7.76 (d, J=5.7Hz, 1H), 7.52 (dd, J=8.8, 2.3 Hz, 1H), 7.46 (t, J=8.7 Hz, 1H), 7.39-7.25(m, 6H), 6.87 (d, J=5.7 Hz, 1H), 3.83 (s, 2H), 3.39 (s, 3H). LCMS: 451.0(M+H)⁺.

TABLE 27 Compounds 426–429(examples 311–314) prepared from the amine 425similarly to the compounds 184 and 185(examples 139–140, scheme 36) CpdEx. Sctructure Characterization 426 311

¹H NMR(400 MHz, DMSO-d₆) δ (ppm): 12.52(s, 1H), 11.86(s, 1H), 9.57(bs,1H), 8.47(d, J=5.6 Hz, 1H), 8.06–7.98(m, 2H), 7.91(s, 1H), 7.71(s, 1H),7.58–7.49(m, 2H), 7.39–7.26(m, 5H), 6.61(d, J=5.6 Hz, 1H), 4.43(t, J=6.0Hz, 2H), 3.83(s, 2H), 3.71–3.63(m, 2H), 3.62–3.42(m, 2H), 3.13– 3.02(m,2H), 2.08–1.96(m, 2H), 1.92–1.78 (m, 2H). LCMS: 601.1(M + H) (formatesalt). N-(3-Fluoro-4-(2-(1-(2-(pyrrolidin-1-yl)ethyl)-1H-imidazol-4-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbainothioyl)-2-phenylacetainide 427 312

¹H NMR(400 MHz, DMSO-d₆) δ (ppm): 12.51(s, 1H), 11.91(s, 1H), 8.47(d,J=5.6 Hz, 1H), 8.56(dd, J=12.4, 2.0 Hz, 1H), 7.97(s, 1H), 7.85(bs, 1H),7.69(s, 1H), 7.60–7.48(m, 3H), 7.40(d, J=4.0 Hz, 2H), 7.36–7.29(m, 1H),6.60(d, J=5.6 Hz, 1H), 4.46(s, 1H), 4.45–4.12(m, 2H), 4.06(s, 2H),3.80–2.20(m, 6H), 2.00–1.60(m, 4H). LCMS:(M + H) 625.22-(2-Ethynylphenyl)-N-(3-fluoro-4-(2-(1-(2-(pyrrolidin-1-yl)ethyl)-1H-imidazol-4-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)acetamide formate 428 313

¹H NMR(400 MHz, DMSO-d₆) δ (ppm): 12.46(s, 1H), 11.85(s, 1H), 8.46(d,J=5.2 Hz, 1H), 8.17(s, 1H), 8.02(dd, J=12.4, 2.0 Hz, 1H), 7.94(d, J=1.2Hz, 1H), 7.79(d, J= 1.2 Hz, 1H), 7.68(s, 1H), 7.56–7.51(m, 2H),7.50–7.44(m, 2H), 7.38–7.34(m, 2H), 6.59(dd, J=5.2, 0.8 Hz, 1H), 4.19(s,1H), 4.13(t, J=6.4 Hz, 2H), 3.87(s, 2H), 3.58– 3.05(m, 4H), 2.80(t,J=6.4 Hz, 2H), 1.68 (q, J=3.2 Hz, 4H). LCMS:(M + H) 625.12-(4-Ethynylphenyl)-N-(3-fluoro-4-(2-(1-(2-(pyrrolidin-1-yl)ethyl)-1H-imidazol-4-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)acetamide formate 429 314

¹H NMR(400 MHz, DMSO-d₆) δ (ppm): 12.47(s, 1H), 11.90(s, 1H), 8.46(d,J=5.6 Hz, 1H), 8.06(dd, J=12.4, 2.4 Hz, 1H), 7.94(d, J=1.2 Hz, 1H),7.79(d, J=1.2 Hz, 1H), 7.68(s, 1H), 7.56(dd, J=8.8, 2.4 Hz, 1H), 7.52(t,J=8.8 Hz, 1H), 7.45(dd, J= 8.4, 5.6 Hz, 1H), 7.37(dd, J=9.2, 2.8 Hz,1H), 7.28(td, J=8.4, 2.4 Hz, 1H), 6.59 4.8 Hz, 1H), 4.60(s, 1H), 4.14(t,J=6.0 Hz, 2H), 4.04(s, 2H), 2.80(t, J=6.0 Hz, 2H), 2.60–2.30(m, 4H,hidden under DMSO), 1.72–1.65(m, 4H). LCMS:(M + H) 643.32-(2-Ethynyl-4-fluorophenyl)-N-(3-fluoro-4-(2-(1-(2-(pyrrolidin-1-yl)ethyl)-1H-imidazol-4-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)acetamide

Example 3152-(7-(2-Fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)thieno[3,2-b]pyridin-2-yl)pyridine1-oxide (430) Step 1: tert-Butyl3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)phenylcarbamate (431)

A solution of 408 (2 g, 4.81 mmol) and NH₄Cl (220 mg, 4.1 mmol) in 2:1mixture of EtOH/water (75 mL) was treated with iron powder (2.28 g, 40.8mmol) and heated to reflux under vigorous stirring for 1 hour. Thereaction mixture was filtered through celite and concentrated. Theresidue was mixed with Boc₂O (5 g, 22.9 mmol) in THF (10 mL) and washeated to reflux for 3 days. The reaction mixture was concentrated andthe crude product was purified by flash chromatography using 40% EtOAcin hexanes as an eluent yielding 1.5 g of 431 (60% yield). LCMS: (M+H)487.0.

Step 2:2-(7-(4-(tert-Butoxycarbonylamino)-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)pyridine1-oxide (432)

A solution of 431 (460 mg, 0.94 mmol), 2-bromopyridine N-oxide (420 mg,2.41 mmol), bistrimethyltin (294 μL, 465 mg, 1.42 mmol) and Pd(PPh₃)₄(109 mg, 0.09 mmol) in dioxane (10 mL) was heated to reflux for 8 hrsunder nitrogen. The reaction mixture was concentrated and purified byflash chromatography using the gradient 5-20% MeOH in EtOAc as an eluentyielding 432 (243 mg, 57% yield). LCMS: (M+H) 454.1.

Steps 3-4:2-(7-(2-Fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)thieno[3,2-b]pyridin-2-yl)pyridine1-oxide (430)

A mixture of 432 (243 mg, 0.53 mmol) in 3:1 mixture of DCM/TFA (8 mL)was stirred at room temperature for 1 hour and concentrated underreduced pressure. The resultant solid was dissolved in 1:1 mixture ofEtOH/toluene (10 mL) and treated with 2-phenylacetyl isothiocyanate (140mg, 0.8 mmol). The reaction mixture was stirred for 1 hour at roomtemperature and concentrated. The residue was purified by flashchromatography using the gradient 0-20% MeOH in EtOAc as an eluentyielding 430 (101 mg, 36% yield). MeOH-d4/CDCl₃ (1:1) 8.5 (d, 1H, J=5.4Hz), 8.38 (m, 3H), 8.0 (d, 1H, 11.9 Hz), 7.62 (t, 1H, J=7.7 Hz), 7.45(m, 2H), 7.2-7.4 (m, 6H), 6.64 (5.1 Hz), 3.75 (s, 2H). LCMS: (M+H)531.2.

TABLE 28 Compounds 433–324(examples 316–319) prepared according to thescheme 86 Cpd Ex. Sctructure Characterization 433 316

¹H NMR(400 MHz, DMSO-d₆) δ (ppm): 8.70(s, 1H), 8.64(dd, J=1.8, 8.2 Hz,1H), 8.59(d, J=5.2 Hz, 1H), 8.48(dd, J=1.0, 5.5 Hz, 1H), 7.99(d, J=12.5Hz, 1H), 7.45–7.60 (m, 4H). 7.36(m, 2H), 7.15(m, 2H), 6.65(d, J=5.5 Hz,1H), 3.82(s, 2H). LCMS: (M + H) 549.1 (100 %) 2-(7-(2-Fluoro-4-(3-(2-(4-fluorophenyl)acetyl)thioureido)phenoxy)thieno[3,2-b]pyridin-2-yl)pyridine 1-oxide 434 317

¹H NMR(400 MHz, DMSO-d₆) δ (ppm): 12.46(s, 1H), 11.82(s, 1H), 8.55(d,J=5.3 Hz, 1H), 8.28(m, 3H), 8.01(d, J=12.7 Hz, 1H), 7.92(d, J=7.2 Hz,2H), 7.53(m, 2H), 7.36(m, 2H), 7.16(t, J=9.0 Hz, 2H), 6.69(d, J=5.1 Hz,1H), 3.81(s, 2H). LCMS:(M + H) 549.24-(7-(2-Fluoro-4-(3-(2-(4-fluorophenyl)acetyl)thioureido)phenoxy)thieno[3 ,2-b]pyridin-2- yl)pyridine 1-oxide 435 318

¹H NMR(400 MHz, DMSO-d₆) δ (ppm): 12.49(s, 1H), 11.88(s, 1H), 8.70(s,1H), 8.65 (dd,J=1.6 Hz, J=8.4 Hz, 1H), 8.59(d, J=5.3 Hz, 1H), 8.48(m,1H), 8.06(dd, J=2.1, 13.1 Hz, 1H), 7.45-7.60(m, SH), 7.38(m, 2H), 7.30(m, 1H), 6.66(dd, J=1.0, 5.3 Hz, 1H), 4.44(s, 1H), 4.04(s, 2H).LCMS:(M + H) 555.1 (100%)2-(7-(4-(3-(2-(2-Ethynylphenyl)acetyl)thioureido)-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)pyridine 1- oxide 436 319

¹H NMR(400 MHz, DMSO-d₆) δ (ppm): 12.46(s, 1H), 11.89(s, 1H), 8.70(s,1H), 8.64 (d, J=6.7 Hz, 1H), 8.59(d, J=5.3 Hz, 1H), 8.48(d, J=6.4 Hz,1H), 8.06(d, J=11.1 Hz, 1H), 7.54(m, 4H), 7.43(m, 1H), 7.35(dd, J= 2.7,9.3 Hz, 1H), 7.26(m, 1H), 6.66(d, J= H, 1H z), 4.57(s, 1H), 4.02(s, 2H).LCMS: (M + H) 573.2 2-(7-(4-(3-(2-(2-Ethynyl-4-fluorophenyl)acetyl)thioureido)-2-fluorophenoxy)thieno[3,2-b]pyridin-2- yl)pyridine 1-oxide

Example 320N-(3-Fluoro-4-(2-(5-((4-methylpiperazin-1-yl)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(437) Step 1:6-(7-(2-Fluoro-4-nitrophenoxy)thieno[3,2-b]pyridin-2-yl)nicotinaldehyde(438)

A solution of 408 (1 g, 2.40 mmol) and 6-bromonicotinaldehyde (450 mg,2.40 mmol) in dioxane (10 mL) was treated sequentially with bistirmethyltin (500 μL, 787 mg, 2.40 mmol) and Pd(PPh₃)₄ (270 mg, 0.24 mmol). Thereaction mixture was heated to reflux under nitrogen overnight andconcentrated. The residue was purified by flash chromatography using thegradient 5%-10% MeOH in DCM as an eluent and subsequent trituration withMeOH, yielding pure 438 (494 mg, 52% yield). ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 10.11 (s, 1H), 9.10 (m, 1H), 8.65 (d, 1H, J=5.2 Hz), 8.62 (s,1H), 8.51 (d, 1H, J=8.8 Hz), 8.48 (dd, 1H, J=2.8 Hz, J=10.4 Hz), 8.38(dd, 1H, J=2.1 Hz, J=8.2 Hz), 8.20 (m, 1H), 7.73 (t, 1H, J=9.0 Hz), 7.01(d, 1H, J=5.5 Hz). LCMS: (M+H) 395.9.

Step 2:7-(2-Fluoro-4-nitrophenoxy)-2-(5-((4-methylpiperazin-1-yl)methyl)pyridin-2-yl)thieno[3,2-b]pyridine(439)

A mixture of 438 (451 mg, 1.14 mmol) and 1-methylpiperazine (152 μL, 137mg, 1. 37 mmol) in DCM (7 mL) was stirred at room temperature for 10min. It was then treated with NaBH(OAc)₃ (340 mg, 1.60 mmol) and stirredat room temperature overnight. The reaction mixture was the diluted withDCM (20 mL) and washed with saturated NaHCO₃ solution (20 mL). It wasthen dried over anhydrous Na₂SO₄, filtered and concentrated. The residuewas purified by flash chromatography using the gradient 30-50% MeOH(with 2% Et₃N) in EtOAc as an eluent, yielding 439 of (308 mg, 52%yield). LCMS: (M+H) 480.0 (100%).

Step 3:3-Fluoro-4-(2-(5-((4-methylpiperazin-1-yl)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-yloxy)aniline(440)

A solution of 439 (306 mg, 0.64 mmol) and NH₄Cl (30 mg, 0.54 mmol) in2:1 mixture of EtOH/water (10.5 mL) was treated with iron powder (304mg, 5.43 mmol) and heated to reflux for 1 hour. The reaction mixture wasthen filtered through celite and concentrated yielding 440 (343 mg, 100%yield) which was used without further purification. LCMS: (M+H) 450.0(100%).

Step 4:N-(3-Fluoro-4-(2-(5-((4-methylpiperazin-1-yl)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(437)

A solution of 440 (100 mg, 0.22 mmol), in 1:1 mixture of EtOH/toluene (2mL) was treated with 2-phenylacetyl isothiocyanate (394 mg, 2.22 mmol)and stirred at room temperature for 2 hours. The reaction mixture wasthen concentrated and purified by flash chromatography using thegradient 10-30% MeOH (containing 2% NH₄OH) in DCM as an eluent, yielding437 (39 mg, 28% yield). DMSO-d6 8.53 (s, 1H), 8.51 (s, 1H), 8.33 (s,1H), 8.23 (d, 1H, J=8.1 Hz), 8.02 (d, 1H, J=11.7 Hz), 7.83 (d, 1H, J=6.6Hz), 7.53 (s, 1H0, 7.2-7.4 (m, 5H), 6.66 (d, 1H, J=5.5 Hz), 3.81 (s,2H), 3.52 (s, 2H), 2.4 (m, 8H), 2.13 (s, 3H), LCMS: (M+H) 627.0 (100%).

TABLE 29 Compounds 329–333(examples 321–326) prepared according to thescheme 87 Cpd Ex. Sctructure Characterization 441 321

¹H NMR(400 MHz, DMSO-d₆) δ (ppm): 12.51(s, 1H), 11.84(s, 1,H), 8.54(d,J=5.3 Hz, 2H), 8.35(s, 1H), 8.25(d, J=8.2 Hz, 1H), 8.03(d, J=13.5 Hz,1H), 7.86(d, J= 7.3 Hz, 1H), 7.53(m, 2H), 7.25–7.35(m, 5H), 6.68(d,J=5.3 Hz, 1H), 3.82(s, 2H), 3.51(s br, 2H), 2.20(s, 6H). LCMS:(M + H)572.2 N-(4-(2-(5-((Dimethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenylcarbamothioyl)-2-phenylacetamide 442 322

¹H NMR(400 MHz, DMSO-d₆) δ (ppm): 12.49(s, 1H), 11.89(s, 1H), 9.01(sbr,2H), 8.70(m, 1H), 8.55(d, 5.4 Hz, 1H), 8.42(s, 1H), 8.36(d, J=8.2 Hz,1H), 8.06(m, 2H), 7.3–7.6(m, 4H), 6.70(ddJ=0.8, 5.3 Hz, 1H,), 4.43(s,1H), 4.25(m, 2H), 4.04(s, 2H), 3.30(s, 3H), 3.15(m, 2H). LCMS: (M + H)626.2 N-(3-Dluoro-4-(2-(5-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-(4-fluorophenyl)acetamide 443 323

¹H NMR(400 MHz, DMSO-d₆) δ (ppm): 12.49(s, 1H), 11.88(s, 1H), 8.70(s,1H), 8.65(dd, J=1.6, 8.4 Hz, 1H), 8.59(d, J=5.3 Hz, 1H), 8.48(m, 1H),8.06(dd, J=2.1 Hz, J=13.1 Hz, 1H), 7.45–7.60(m, SH), 7.38 (m, 2H),7.30(m, 1H), 6.66(dd, J=1.0, 5.3 Hz, 1H), 4.44(s, 1H), 4.04(s, 2H).LCMS: (M + H) 555.1 2-(2-Ethynylphenyl)-N-(3-fluoro-4-(2-(5-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)acetamide 444 324

¹H NMR(400 MHz, DMSO-d₆) δ (ppm): 8.54(br.s, 1H), 8.53(d, J=5.4 Hz, 1H),8.32(s, 1H), 8.22(d, J=8.0 Hz, 1H), 8.00 (d, J=12.5 Hz, 1H), 7.86(dd,J=2.0, 8.2 Hz, 1H), 7.50(m, 2H), 7.36(m, 2H), 7.25 (m, 1H), 7.16(t,J=8.8 Hz, 2H), 7.05(t, J= 8.8 Hz, 1H), 6.66(d, 1H, J=5.5 Hz), 3.82 (s,2H0, 3.57(s, 2H), 3.50(m, 2H), 2.43(t, J=6.3 Hz, 2H), 2.17(s, 3H). LCMS:(M + H) 620.2 N-(3-Fluoro-4-(2-(5-(((2-hydroxyethyl)(methyl)amino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-(4-fluorophenyl) acetamide 445 325

¹H NMR(400 MHz, DMSO-d₆) δ (ppm): 12.48(s, 1H), 11.84(s, 1H), 9.33(br.s,12H), 8.63(d, J=5.9 Hz, 1H), 8.49(s, 1H), 8.31(d, J=7.9 Hz, 1H), 8.05(m,2H), 7.57 (m, 2H), 7.37(m, 2H), 7.17(t, J=9.0 Hz, 2H), 6.79(d, J=5.7 Hz,1H), 4.41(m, 2H), 3.82(s, 3H), 3.68(m, 2H0, 3.28(m, 4H). LCMS:(M + H)620.2 N-(3-Fluoro-4-(2-(6-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-(4-fluorophenyl)acetamide 446 326

δ (400 MHz, DMSO-d₆): 12.51(s, 1H), 11.81(s, 1H), 8.54(m, 2H), 8.33(s,1H), 08.23(d, J=8.0 Hz, 1H), 8.01–8.05(m, 1H), 7.86(dd, J=1.8, 8.0 Hz, 1H), 7.50– 7.57(m, 2H), 7.32–7.37(m, 4H), 7.24– 7.32(m, 1H), 6.68(d,J=5.3 Hz, 1H), 3.83(s, 2H), 3.64(s, 2H), 2.46(m, 4H), 1.70(m, 4H).N-(3-Fluoro-4-(2-(5-(pyrrolidin-1-ylmethyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide

Example 260N-(3-Fluoro-4-(2-(3-methoxyphenylamino)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-(2-methoxyphenyl)acetamide(447) Step 1:7-(2-Fluoro-4-nitrophenoxy)-N-(3-methoxyphenyl)thieno[3,2-b]pyridin-2-amine(448)

A solution of 408 (700 mg, 1.68 mmol), Cs₂CO₃ (1.12 g, 3.43 mmol),3-methoxyaniline (190 μL, 206 mg, 1.68 mmol), Pd(OAc)₂ (70 mg, 0.17mmol) and Xantphos (1.43 g, 2.52 mmol) (J. Org. Chem. 1999, 64,6019-6022) in dioxane (15 mL) was heated to reflux for 5 hrs. Thereaction mixture was then concentrated and purified by flashchromatography using 80% EtOAc in hexanes as an eluent yielding 448 of(408 mg, 59% yield). LCMS: (M+H) 412.0.

Step 2:7-(4-Amino-2-fluorophenoxy)-N-(3-methoxyphenyl)thieno[3,2-b]pyridin-2-amine(449)

A solution of 448 (408 mg, 0.99 mmol) and NH₄Cl (45 mg, 084 mmol) in 2:1mixture of EtOH/water (15 mL) was treated with iron powder (472 mg, 8.43mmol) and heated to reflux under vigorous stirring for 1 hour. Thereaction mixture was then filtered through celite and concentratedyielding 449 which was used without further purification (278 mg, 74%yield). LCMS: (M+H) 382.0.

Steps 3:N-(3-Fluoro-4-(2-(3-methoxyphenylamino)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-(2-methoxyphenyl)acetamide(447)

A solution of 449 (40 mg, 0.10 mmol) in 1:1 mixture of EtOH/toluene (2mL) was treated with 2-(2-methoxyphenyl)acetyl isothiocyanate (394 mg,2.22 mmol) and stirred at room temperature for 2 hours. The reactionmixture was then concentrated and purified by flash chromatography usingthe gradient 75-100% EtOAc in hexanes as an eluent, yielding 447 (15 mg,24% yield). CDCl₃ 12.39 (s, 1H), 9.47 (s, 1H), 8.34 (d, J=5.7 Hz, 1H),7.92 (dd, J=2.0, 11.8 Hz, 1H), 7.36 (m, 2H), 7.22 (m, 2H), 7.01 (m, 3H),6.80 (s, 2H), 6.59 (d, J=7.4 Hz, 2H), 6.39 (d, J=5.6 Hz, 1H), 4.00 (s,3H), 3.80 (s, 3H), 3.72 (s, 2H) LCMS: (M+H) 589.0

Example 328N-(3-Fluoro-4-(2-(4-(piperazin-1-ylmethyl)phenyl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-2-oxo-3-phenylimidazolidine-1-carboxamide(450) Step 1. tert-Butyl 4-(4-bromobenzyl)piperazine-1-carboxylate (451)

1-Bromo-4-(bromomethyl)benzene (8.078 g, 32.3 mmol) and tert-butylpiperazine-1-carboxylate (6.625 g, 35.6 mmol) were dissolved in DMF (40ml) and K₂CO₃ (8.93 g, 64.6 mmol) was added. The reaction mixture washeated to 60° C. for 4 h and then filtered through a pad of celite. Thefiltrate was evaporated and the residue was triturated in hexanes toproduce compound 451 as white solid (9.46 g, 82% yield). LCMS: 255.0(M+H)⁺.

Step 2. tert-Butyl4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)piperazine-1-carboxylate(452)

Compound 451 (9.46 g, 26.63 mmol), KOAc (7.84 g, 79.88 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (10.14 g,39.95 mmol), Pd(PPh₃)₄ (3.07 g, 2.663 mmol) and toluene (133 mL) wereplaced into a 250 mL round bottom flask. The reaction mixture was purgedwith nitrogen for a half-an-hour and heated to reflux for 4 h. It wasthen cooled to RT, diluted with EtOAc (400 mL) and washed with H₂O (100mL), dried over Na₂SO₄, filtered, concentrated to afford title compound452 as brown oil (22.36 g, >100% yield). LCMS: 403 (M+H)⁺. This materialwas used in the next step with no additional purification.

Step 3. tert-Butyl4-(4-(7-(2-fluoro-4-nitrophenoxy)thieno[3,2-b]pyridin-2-yl)benzyl)piperazine-1-carboxylate(453)

Compound 452 (22.36 g, 26.6 mmol), iodide 408 (7.904 g, 19.0 mmol), CsF(8.658 g, 57 mmol), NaHCO₃ (4.788 g, 57 mmol) and Pd(PPh₃)₄ (2.195 g,1.9 mmol) were combined with a mixture of H₂O (25 mL) and DME (100 mL)which was with nitrogen for a half-an-hour and heated to refluxovernight. It was then was cooled to RT, diluted with EtOAc (200 ml),washed with aqueous NaHCO₃ (50 mL) and brine (50 mL), and concentrated.The residue was purified by flash column chromatography (eluent pureEtOAc to 5% MeOH/EtOAc) followed by trituration with EtOAc/ether, toproduce compound 453 as an off-white solid (5.4 g, 50% yield). LCMS: 565(M+H)⁺.

Step 4. tert-Butyl4-(4-(7-(4-amino-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)benzyl)piperazine-1-carboxylate(454)

Compound 453 (5.4 g, 9.56 mmol), iron powder (1.602 g, 28.69 mmol) andNH₄Cl (0.78 g, 14.34 mmol) were placed in a mixture of H₂O (24mL) andEtOH (48 mL). The reaction mixture was heated to reflux for 5 h. It wasthen cooled to RT, diluted with MeOH and filtered through a pad ofcelite. The filtrate was concentrated to dryness and the residue wasdissolved in dichloromethane, washed with aqueous NaHCO₃ and brine,dried over Na₂SO₄, and filtered. The filtrate was concentrated todryness to give compound 454 as white solid (4.2 g, 83% yield). LCMS:535 (M+H)⁺.

Step 5.N-(3-Fluoro-4-(2-(4-(piperazin-1-ylmethyl)phenyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(450)

Compound 454 (0.3323 g, 0.62 mmol) was suspended in EtOH/toluene (3 mL/3mL) at RT and stirred for 30 min. 2-Phenylacetyl isothiocyanate (0. 165g, 0.93 mmol) was added and the reaction mixture was stirred at RT for 1h, quenched with MeOH (2 mL) and concentrated to dryness. The residuewas purified by flash chromatography (eluent 9/1/90 MeOH/NH₄OH/DCM) togive compound 450 as a white solid (60 mg, 16% yield). ¹H NMR δ(400 MHz,CD₃CN): 8.51 (d, J=5.5 Hz, 1H), 7.99 (dd, J=2.5, 12.3 Hz, 1H), 7.84 (s,1H), 7.82 (d, J=8.2 Hz, 2H), 7.32-7.53 (m, 9H), 6.62 (d, J=4.5 Hz, 1H),3.81 (s, 2H), 3.54 (s, 2H), 2.30-2.53 (bs, 8H), 2.22 (s, 3H). LCMS: 613(M+H)⁺.

Example 3294-(4-(7-(2-Fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)thieno[3,2-b]pyridin-2-yl)benzyl)-N-methylpiperazine-1-carboxamide(455)

Compound 450 (0.367 g, 0.60 mmol) was dissolved in dichloromethane (2mL) at RT and then Et₃N (0.25 mL, 1.803 mmol) was added. The reactionmixture was cooled to 0° C., treated with isocyanatomethane (0. 16 mL,3.43 mmol) and stirred for 10 min at 0° C. The reaction mixture was thenwarmed to RT over a 30 min period, and then was quenched with MeOH. Itwas then concentrated to dryness and the residue was purified by flashchromatography (eluent 9/1/10 MeOH/NH₄Cl/DCM) to give title compound 455as a pale yellow solid (0.16 g, 39% yield). ¹H NMR δ (400 MHz, DMSO-d6):12.48 (s, 1H), 11.83 (s, 1 H), 8.51 (dd, J=1.2, 5.5 Hz, 1H), 8.01 (m,2H), 7.84 (m, 2H), 7.53 (m, 2H), 7.42 (d, J=8.4 Hz, 2H), 7.23-7.38 (m,5H) 6.65 (dd, J=0.8, 5.5 Hz, 1H), 6.39 (q, J=4.2 Hz, 1 H), 3.81 (s, 2H), 3.51 (s, 2H), 3.25 (m, 4H), 2.53 (d, J=4.3 Hz, 3H), 2.31 (m, 4H).LCMS: 669 (M+H)⁺.

Example 330N-Ethyl-4-(4-(7-(2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)thieno[3,2-b]pyridin-2-yl)benzyl)piperazine-1-carboxamide(456)

Title compound 456 was obtained similarly to the compound 455 accordingto the scheme 90, in 82% yield. ¹H NMR δ (400 MHz, DMSO-d6): ): 8.53(dd, J=0.5, 5.4 Hz, 1H), 8.05 (s, 1H), 8.01 (d, J=12.5 Hz, 1H), 7.85 (d,J=8.2 Hz, 2H), 7.50-7.58 (m, 2H), 7.44 (d, J=8.0 Hz, 2H), 7.32-7.38 (m,4H), 7.24-7.32 (m, 1H), 6.65 (d, J=5.3 Hz, 1H), 6.44 (t, J=5.5 Hz, 1H),3.83 (s, 2H), 3.52 (s, 2H), 3.27 (m, 4H), 2.97-3.60 (m, 2H), 2.32 (m,4H), 0.98 (t, J=7.1 Hz, 3H). LCMS: 683 (M+H)⁺.

ASSAY EXAMPLES Assay Example 1 Inhibition of c-met and VEGF Activity

The following protocols were used to assay the compounds of theinvention.

In Vitro Receptor Tyrosine Kinase Assays (c-Met/HGF Receptor and VEGFReceptor KDR)

These tests measure the ability of compounds to inhibit the enzymaticactivity of recombinant human c-Met/HGF receptor and VEGF receptorenzymatic activity.

A 1.3-kb cDNA corresponding to the intracellular domain of c-Met orc-Met IC (Genbank accession number NP000236-1 amino acid 1078 to 1337)was cloned into the BamHI/XhoI sites of the pBlueBacHis2A vector(Invitrogen) for the production of a histidine-tagged version of thatenzyme. This constuct was used to generate recombinant baculovirus usingthe Bac-N-Blue™ system according to the manucfacturer's instructions(Invitrogen)

The c-Met IC protein was expressed in Hi-5 cells (Trichoplusia Ni) uponinfection with recombinant baculovirus construct. Briefly, Hi-5 cellsgrown in suspension and maintained in serum-free medium (Sf900 IIsupplemented with gentamycin) at a cell density of about 2×10⁶ cells/mlwere infected with the abovementioned viruses at a multiplicity ofinfection (MOI) of 0.2 during 72 hours at 27° C. with agitation at 120rpm on a rotary shaker. Infected cells were harvested by centrifugationat 398 g for 15 min. Cell pellets were frozen at −80° C. untilpurification was performed.

All steps described in cell extraction and purification were performedat 4° C. Frozen Hi-5 cell pellets infected with the C-Met IC recombinantbaculovirus were thawed and gently resuspended in Buffer A (20 mM TrispH 8.0, 10% glycerol, 1 μg/ml pepstatin, 2 μg/ml Aprotinin andleupeptin, 50 μg/ml PMSF, 50 μg/ml TLCK and 10 μM E64, 0.5 mM DTT and 1mM Levamisole) using 3 ml of buffer per gram of cells. The suspensionwas Dounce homogenized after which it was centrifuged at 22500 g, 30min., 4° C. The supernatant (cell extract) was used as starting materialfor purification of c-Met IC.

The supernatant was loaded onto a QsepharoseFF column (AmershamBiosciences) equilibrated with Buffer B (20 mM Tris pH 8.0, 10%glycerol) supplemented with 0.05M NaCl. Following a ten column volume(CV) wash with equilibration buffer, bound proteins were eluted with a 5CV salt linear gradient spanning from 0.05 to 1M NaCl in Buffer B.Typically, the conductivity of selected fractions ranked between 6.5 and37 mS/cm. This Qsepharose eluate had an estimated NaCl concentration of0.33M and was supplemented with a 5M NaCl solution in order to increaseNaCl concentration at 0.5M and also with a 5M Imidazole (pH 8.0)solution to achieve a final imidazole concentration of 15mM. Thismaterial was loaded onto a HisTrap affinity column (GE Healthcare)equilibrated with Buffer C (50 mM NaPO₄ pH 8.0, 0.5M NaCl, 10% glycerol)supplemented with 15mM imidazole. After a 10 CV wash with equilibrationbuffer and an 8 CV wash with buffer C+40 mM imidazole, bound proteinswere eluted with an 8 CV linear gradient (15 to 500 mM) of imidazole inbuffer C. C-Met IC enriched fractions from this chromatography step werepooled based on SDS-PAGE analysis. This pool of enzyme underwent bufferexchange using PD-1I column (GE Healthcare) against buffer D (25 mMHEPES pH 7.5, 0.1M NaCl, 10% glycerol and 2mM □-mercaptoethanol) FinalC-Met IC protein preparations concentrations were about 0.5 mg/ml withpurity approximating 80%. Purified c-Met IC protein stocks weresupplemented with BSA at 1 mg/ml, aliquoted and frozen at −80° C. priorto use in enzymatic assay.

In the case of VEGF receptor KDR a 1.6-kb cDNA corresponding to thecatalytic domain of VEGFR2 or KDR (Genbank accession number AF035121amino acid 806 to 1356) was cloned into the Pst I site of the pDEST20Gateway vector (Invitrogen) for the production of a GST-tagged versionof that enzyme. This constuct was used to generate recombinantbaculovirus using the Bac-to-Bac™ system according to themanucfacturer's instructions (Invitrogen)

The GST-VEGFR2₈₀₆₋₁₃₅₆ protein was expressed in Sf9 cells (Spodopterafrugiperda) upon infection with recombinant baculovirus construct.Briefly, Sf9 cells grown in suspension and maintained in serum-freemedium (Sf900 II supplemented with gentamycin) at a cell density ofabout 2×10⁶ cells/ml were infected with the abovementioned viruses at amultiplicity of infection (MOI) of 0.1 during 72 hours at 27° C. withagitation at 120 rpm on a rotary shaker. Infected cells were harvestedby centrifugation at 398 g for 15 min. Cell pellets were frozen at −80°C. until purification was performed.

All steps described in cell extraction and purification were performedat 4° C. Frozen Sf9 cell pellets infected with the GST-VEGFR2₈₀₆₋₁₃₅₆recombinant baculovirus were thawed and gently resuspended in Buffer A(PBS pH 7.3 supplemented with 1 μg/ml pepstatin, 2 μg/ml Aprotinin andleupeptin, 50 μg/ml PMSF, 50 μg/ml TLCK and 10 μM E64 and 0.5 mM DTT)using 3 ml of buffer per gram of cells. Suspension was Douncehomogenized and 1% Triton X-100 was added to the homogenate after whichit was centrifuged at 22500 g, 30 min., 4° C. The supernatant (cellextract) was used as starting material for purification ofGST-VEGFR2₈₀₆₋₁₃₅₆.

The supernatant was loaded onto a GST-agarose column (Sigma)equilibrated with PBS pH 7.3. Following a four column volume (CV) washwith PBS pH 7.3+1% Triton X-100 and 4 CV wash with buffer B (50 mM TrispH 8.0, 20% glycerol and 100 mM NaCl), bound proteins were step elutedwith 5 CV of buffer B supplemented with 5mM DTT and 15 mM glutathion.GST-VEGFR2₈₀₆₋₁₃₅₆ enriched fractions from this chromatography step werepooled based on U.V. trace i.e. fractions with high O.D.₂₈₀. FinalGST-VEGFR2₈₀₆₋₁₃₅₆ protein preparations concentrations were about 0.7mg/ml with purity approximating 70%. Purified GST-VEGFR2₈₀₆₋₁₃₅₆ proteinstocks were aliquoted and frozen at −80° C. prior to use in enzymaticassay.

Inhibition of c-Met/HGF receptor and VEGFR/KDR was measured in a DELFIA™assay (Perkin Elmer). The substrate poly(Glu₄,Tyr) was immobilized ontoblack high-binding polystyrene 96-well plates. The coated plates werewashed and stored at 4° C. During the assay, enzymes were pre-incubatedwith inhibitor and Mg-ATP on ice in polypropylene 96-well plates for 4minutes, and then transferred to the coated plates. The subsequentkinase reaction took place at 30° C. for 10-30 minutes. ATPconcentrations in the assay were 10 uM for C-Met (5× the K_(m)) and 0.6uM for VEGFR/KDR (2× the K_(m)). Enzyme concentration was 25 nM (C-Met)or 5 nM (VEGFR/KDR). After incubation, the kinase reactions werequenched with EDTA and the plates were washed. Phosphorylated productwas detected by incubation with Europium-labeled anti-phosphotyrosineMoAb. After washing the plates, bound MoAb was detected by time-resolvedfluorescence in a Gemini SpectraMax reader (Molecular Devices).Compounds were evaluated over a range of concentrations and IC₅₀'s(concentration of compounds giving 50% inhibition of enzymatic activity)were determined.

C-Met Phosphorylation Cell-Based Assay

This test measures the ability of compounds to inhibit HGF stimulatedauto-phosphorylation of the c-Met/HGF receptor itself in a whole cellsystem.

MNNGHOS cell line expressing TPR-MET fusion protein were purchased fromATCC. The TPR-MET is the product of a chromosomal translocation placingthe TPR locus on chromosome 1 upstream of the MET gene on chromosome 7encoding for it's cytoplasmic region catalytic domain. Dimerization ofthe M_(r) 65,000 TPR-Met oncoprotein through a leucine zipper motifencoded by the TPR portion leads to constitutive activation of the metkinase. Constitutive autophosphorylation occurs on residuesTyr361/365/366 of TPR-Met. These residues are homologous toTyr1230/1234/1235 of MET which become phosphorylated upon dimerizationof the receptor upon HGF binding.

Inhibitor of c-Met formulated as 30 mM stocks in DMSO. For MNNGHOStreatments, cells, compounds were added to tissue culture media atindicated doses for 3 hours prior to cell lysis. Cells were lysed inice-cold lysis buffer containing 50 mM HEPES (pH 7.5), 150 mM NaCl, 1.5mM MgCl2, 10% glycerol, 1% Triton X-100, 1 mM4-(2-Aminoethyl)benzenesulfonyl fluoride hydrochloride, 200 μM sodiumorthovanadate, 1 mM sodium fluoride, 10 μg/ml of leupeptin, 10 μg/ml ofaprotinin/ml, 1 ug/ml of pepstatin and 50 ug/ml Na-p-Tosyl-L-lysinechloromethyl ketone hydrochloride.

Lysate were separated on 5-20% PAGE-SDS and immunoblots were performedusing Immobilon P polyvinylidene difluoride membranes (Amersham)according to the manufacturer's instructions for handling. The blotswere washed in Tris-buffered saline with 0.1% Tween 20 detergent (TBST).Tyr361/365/366 of TPR-Met were detected with polyclonal rabbitantibodies against tyrosine phosphorylated Met (Biosource International)and secondary antibodies anti-rabbit-horseradish peroxidase (Sigma) bychemiluminescence assays (Amersham, ECL) were performed according to themanufacturer's instructions and followed by film exposure. Signal wasquantitated by densitometry on Alpha-Imager. IC₅₀ values were defined asthe dose required to obtain 50% inhibition of the maximal HGF stimulatedphosphorylated c-Met levels.

In Vivo Solid Tumor Disease Model

This test measures the capacity of compounds to inhibit solid tumorgrowth.

Tumor xenografts were established in the flank of female athymic CD1mice (Charles River Inc.), by subcutaneous injection of 1×10⁶ U87, A431or SKLMS cells/mouse. Once established, tumors were then seriallypassaged s.c. in nude mice hosts. Tumor fragments from these hostanimals were used in subsequent compound evaluation experiments. Forcompound evaluation experiments female nude mice weighing approximately20 g were implanted s.c. by surgical implantation with tumor fragmentsof ˜30 mg from donor tumors. When the tumors were approximately 100 mm³in size (˜7-10 days following implantation), the animals were randomizeda separated into treatment and control groups. Each group contained 6-8tumor-bearing mice, each of which was ear-tagged and followedindividually throughout the experiment

Mice were weighed and tumor measurements are taken by calipers threetimes weekly, starting on Day 1. These tumor measurements were convertedto tumor volume by the well-known formula (L+W/4)³ 4/37π. The experimentwas terminated when the control tumors reached a size of approximately1500 mm³. In this model, the change in mean tumor volume for a compoundtreated group/the change in mean tumor volume of the control group(non-treated or vehicle treated)×100 (ΔT/ΔC) was subtracted from 100 togive the percent tumor growth inhibition (% TGI) for each test compound.In addition to tumor volumes, body weight of animals were monitoredtwice weekly for up to 3 weeks.

The activities of a number of compounds according to the inventionmeasured by various assays are displayed in the following tables, Table30 and Table 31. In these tables, “a” indicates inhibitory activity at aconcentration of less than 50 nanomolar; “b” indicates inhibitoryactivity at a concentration≧50 but <250 nanomolar, “c” indicatesinhibitory activity at ≧250 but <500 and “d” indicates inhibitoryactivity at a concentration of ≧500 nanomolar; and “e” indicates noactivity as measured by that assay.

HGF has well known activity in terms of inducing scattering andmigration (wound healing) (Wells et al., Cell Motil Cytoskeleton. 2005November 62(3):180-94; Miura et al., Urology December 2001 December58(6):1064-9; Nishimura et al., Int J Urol. 1998 May 5(3):276-81; Wanget Cancer Ther. November 2003; 2(11):1085-92; and Christensen et al.,Cancer Res. November 2003 1; 63(21):7345-55). Assays to evaluateinhibitor ability to block these HGF dependent activities have beenemployed and follow the methods employed in Christensen et al. For Table31, for columns directed to A549 wound healing inhibition and DU145scattering inhibition, IC₅₀ with “A” indicating IC₅₀ of less than 1 mM,“B” indicating IC₅₀ of >1 mM indicating IC₅₀ of ≧5 mM but <10 mM, and“D” indicating IC₅₀ of ≧10 mM.

TABLE 30 C-Met cell-based Y1230-34-35 tpr- Example Compound C-Met (enz.)VEGF(enz.) met inhibition No No (IC₅₀, nM) (IC₅₀, nM) (IC₅₀, nM) 1 8a ba a 2 8b b a b 3 8c b c b 5 8e b b b 7 8g b c b 9 8i b b c 10 8j b b b11 8k b d b 12 13a b a a 13 13b b a a 14 13c b b b 15 13d b a a 133 170ab b b 16 13e b a c 18 13g b b b 20 18a b d e 22 26a b b a 23 26b b a b24 26c b c d 25 26d b b e 26 26e b b e 27 26f b b e 28 31a b d e 29 31bc d e 35 8m b b a 36 8n b d b 37 8o b a a 40 8r b a b 75 13k b a a 14226f b a a 188 170c c d d 221 269a a d d

TABLE 31 A549 wound healing DU145 inhib scattering CMet VEGFR IC50 inhibIC50 Structure ic50 (nM) IC50 (nM) (mM) (mM)

b b D B

a a B B

a B A

a b B B

b b A A

c d C C

a d A A

b d A B

a d A A

a a A A

a d A A

a a A A

a a C A

b d B B

a a A A

a a A A

a d A A

a c A A

a a B A

a a A A

a a B A

a c A A

a a A A

a a A A

a b A A

a a A A

a a A A

a a A A

a a A A

a a A A

a c A A

a a A A

a a A A

a a A

a b A A

a a A A

a a A A

b b B D

a a A A

a a A A

a b A A

b a B B

a a A A

b a D D

a a A A

a b A A

a a A A

a a B B

b a D D

b a D B

b a A B

a a B B

a a B B

a a A A

a a A A

b a D B

a a A A

b d D B

a a A A

a a A A

a a B A

a a A A

a a A A

a b A A

a c A A

a a A A

a a A A

a a A A

a a A A

a b A A

a a A A

a a A A

a a A A

b b B B

a a A A

a a A A

a b A A

a a A A

a A A

a c A A

a a A

a b A A

A A

A A

In the following tables, Table 32 and Table 33, “a” indicates % TGI inthe range of 75-100; “b” indicates % TGI in the range of 50-74; “c”indicates % TGI in the range of 25-49, and “d” indicates % TGI in therange of 0-24. Regiment of administration was once daily.

TABLE 32 Dosage mg/kg Duration of Tumor Growth (once experiment Route ofInhibition Ex (Cpd) daily) Vehicle Tumor type (days) administration (%) 1 (8a) 30 DMSO A431 14 IP d 30 DMSO A549 14 IP b 100 5% DMSO - 1%Tween-80 in water U87MG 14 PO c 15 DMSO MKN74 10 IP d 30 DMSO MKN74 10IP c 15 DMSO U87MG 10 IP c 30 DMSO U87MG 7 IP c 30 DMSO A431 14 IP c 30DMSO U87MG 14 IP c 30 DMSO SKLMS40 14 IP b 30 DMSO SW48 14 IP b 30 DMSOU87MG 14 IP a* 30 DMSO HCT116 14 IP c  7 (8g) 30 DMSO SW48 14 IP c 30DMSO HCT116 14 IP b  12 (13a) 30 DMSO SW48 14 IP b 30 DMSO U87MG 14 IP b30 DMSO HST116 14 IP c 30 DMSO SW48 14 IP d  13 (13b) 30 DMSO A431 7 IPb 30 DMSO SW48 14 IP d 30 DMSO U87MG 14 IP a 30 DMSO DU145 10 IP d 30DMSO SKLMS40 10 IP b  37 (8o) 15 DMSO DU145 10 IP d 30 DMSO DU145 10 IPd 30 DMSO A431 14 IP b 30 DMSO A549 14 IP c 15 50/50 DMSO:40/60 PEG/0.2N HCl in saline U87MG 10 IV b 30 50/50 DMSO:40/60 PEG/0.2 N HCl insaline U87MG 10 IV c  15 (13d) 30 DMSO DU145 10 IP b 30 DMSO SKLMS40 10IP b 30 DMSO A431 14 IP b 30 DMSO A549 14 IP b 15 DMSO DU145 10 IP d 30DMSO DU145 10 IP d 15 50/50 DMSO:40/60 PEG/0.2 N HCl in saline U87MG 10IV b 30 50/50 DMSO:40/60 PEG/0.2 N HCl in saline U87MG 10 IV b 100 5%DMSO - 1% Tween-80 in water U87MG 14 PO a 30 DMSO U87MG 14 IP b 75 5%DMSO - 1% Tween-80 in water A549 12 PO c 50 5% DMSO - 1% Tween-80 inwater A549 11 PO c 75 5% DMSO - 1% Tween-80 in water A549 10 PO b 15DMSO MKN74 10 IP c 30 DMSO MKN74 10 IP c 15 DMSO U87MG 10 IP b 30 DMSOU87MG 10 IP b 15 DMSO HCT116 10 IP c 30 DMSO HCT116 10 IP c  75 (13k) 15DMSO DU145 10 IP c 15 DMSO SKLMS40 10 IP b 100 5% DMSO - 1% Tween-80 inwater U87MG 14 PO b 30 DMSO U87MG 14 IP c 75 5% DMSO - 1% Tween-80 inwater A549 12 PO b 30 DMSO U87MG 10 IP c 15 DMSO U87MG 10 IP d  73 (13i)100 5% DMSO - 1% Tween-80 in water U87MG 14 PO c  38 (8p) 30 DMSO A43114 IP c 30 DMSO A549 14 IP c  39 (8q) 30 DMSO A549 14 IP b 148 (26l) 30DMSO DU145 10 IP c 30 50/50 DMSO:40/60 PEG/0.2 N HCl in saline U87MG 10IP c  76 (13l) 75 5% DMSO - 1% Tween-80 in water A549 10 PO b 75 5%DMSO - 1% Tween-80 in water DU145 10 PO c 30 DMSO A549 14 IP b 75 5%DMSO - 1% Tween-80 in water A549 14 PO c 157 (195b) 30 DMSO A341 14 IP c30 DMSO A549 14 IP c  56 (55) 30 DMSO A549 12 IP c  63 (76c) 30 DMSOA549 10 IP b 30 DMSO DU145 10 IP c  77 (13m) 30 DMSO A549 10 IP b 75 5%DMSO - 1% Tween-80 in water A549 10 PO b 75 5% DMSO - 1% Tween-80 inwater U87MG 14 PO b 75 5% DMSO - 1% Tween-80 in water SKLMS40 6 PO d 201(227) 30 DMSO A549 10 IP c 75 5% DMSO - 1% Tween-80 in water A549 10 POc  81 (13q) 75 5% DMSO - 1% Tween-80 in water SKLMS40 14 PO c 242 (310a)75 5% DMSO - 1% Tween-80 in water U87MG 14 PO a 75 5% DMSO - 1% Tween-80in water HCT116 14 PO b 243 (310b) 75 5% DMSO - 1% Tween-80 in waterU87MG 14 PO b 75 5% DMSO - 1% Tween-80 in water SKLMS40 11 PO b 137(178) 75 0.5% CMC in acetate buffer (pH 4.0) MDA-MB- 14 PO b 231 138(179) 75 0.5% CMC in acetate buffer (pH 4.0) MDA-MB- 14 PO b 231 a* -greater than 100% tumor growth inhibition (i.e., tumor shrinkage)

TABLE 33 Dosage mg/kg Duration of Tumor Growth (once experimentInhibition Structure daily) Tumor type (days) (%)

40 (p.o.) MNNG-HOS 14 a

75 (p.o.) MNNG-HOS 14 a*

20 (p.o.) MNNG-HOS 14 c

40 (p.o.) A549 14 b

20 (p.o.) MV4-11 14 a a* - greater than 100% tumor growth inhibition(i.e., tumor shrinkage)

1. A compound selected from the group consisting of

and pharmaceutically acceptable salts thereof.
 2. A compound selectedfrom the group consisting of

and pharmaceutically acceptable salts thereof.
 3. A compound selectedfrom the group consisting of

and pharmaceutically acceptable salts thereof.
 4. A compound selectedfrom the group consisting of

and pharmaceutically acceptable salts thereof.
 5. A compound selectedfrom the group consisting of

and pharmaceutically acceptable salts thereof.
 6. A compound selectedfrom the group consisting of

and pharmaceutically acceptable salts thereof.
 7. The compound accordingto claim 1, having the structure


8. The compound according to claim 1, having the structure


9. The compound according to claim 1, having the structure


10. The compound according to claim 1, having the structure


11. The compound according to claim 1, having the structure


12. The compound according to claim 1, having the structure


13. The compound according to claim 1, having the structure


14. The compound according to claim 1, having the structure


15. The compound according to claim 1, having the structure


16. The compound according to claim 1, having the structure


17. The compound according to claim 1, having the structure


18. The compound according to claim 2, having the structure


19. The compound according to claim 3, having the structure


20. The compound according to claim 3, having the structure


21. The compound according to claim 3, having the structure


22. The compound according to claim 3, having the structure


23. The compound according to claim 3, having the structure


24. The compound according to claim 5, having the structure


25. The compound according to claim 5, having the structure


26. The compound according to claim 5, having the structure


27. The compound according to claim 6, having the structure


28. The compound according to claim 6, having the structure


29. The compound according to claim 6, having the structure


30. The compound according to claim 6, having the structure


31. The compound according to claim 6, having the structure


32. An N-oxide of a compound according to claim
 1. 33. An N-oxide of acompound according to claim
 2. 34. An N-oxide of a compound according toclaim
 3. 35. An N-oxide of a compound according to claim
 4. 36. AnN-oxide of a compound according to claim
 5. 37. An N-oxide of a compoundaccording to claim
 6. 38. A pharmaceutical composition comprising acompound according to claim 1 and a pharmaceutically acceptable carrier.39. A pharmaceutical composition comprising a compound according toclaim 2 and a pharmaceutically acceptable carrier.
 40. A pharmaceuticalcomposition comprising a compound according to claim 3 and apharmaceutically acceptable carrier.
 41. A pharmaceutical compositioncomprising a compound according to claim 4 and a pharmaceuticallyacceptable carrier.
 42. A pharmaceutical composition comprising acompound according to claim 5 and a pharmaceutically acceptable carrier.43. A pharmaceutical composition comprising a compound according toclaim 6 and a pharmaceutically acceptable carrier.
 44. A method ofinhibiting VEGF receptor signaling and HGF receptor signaling in ananimal, the method comprising administering to the animal a receptorinhibiting amount of a compound according to claim 1, or an N-oxidethereof or a composition comprising said compound or an N-oxide thereofand a pharmaceutically acceptable carrier.
 45. A method of inhibitingVEGF receptor signaling and HGF receptor signaling in an animal, themethod comprising administering to the animal a receptor inhibitingamount of a compound according to claim 2, or an N-oxide thereof or acomposition comprising said compound or an N-oxide thereof and apharmaceutically acceptable carrier.
 46. A method of inhibiting VEGFreceptor signaling and HGF receptor signaling in an animal, the methodcomprising administering to the animal a receptor inhibiting amount of acompound according to claim 3, or an N-oxide thereof or a compositioncomprising said compound or an N-oxide thereof and a pharmaceuticallyacceptable carrier.
 47. A method of inhibiting VEGF receptor signalingand HGF receptor signaling in an animal, the method comprisingadministering to the animal a receptor inhibiting amount of a compoundaccording to claim 4, or an N-oxide thereof or a composition comprisingsaid compound or an N-oxide thereof and a pharmaceutically acceptablecarrier.
 48. A method of inhibiting VEGF receptor signaling and HGFreceptor signaling in an animal, the method comprising administering tothe animal a receptor inhibiting amount of a compound according to claim5, or an N-oxide thereof or a composition comprising said compound or anN-oxide thereof and a pharmaceutically acceptable carrier.
 49. A methodof inhibiting VEGF receptor signaling and HGF receptor signaling in ananimal, the method comprising administering to the animal a receptorinhibiting amount of a compound according to claim 6, or an N-oxidethereof or a composition comprising said compound or an N-oxide thereofand a pharmaceutically acceptable carrier.
 50. A method of treating anangiogenesis-mediated cell proliferative disease in a patient orinhibiting solid tumor growth in a patient, the method comprisingadministering to the patient in need thereof an effective therapeuticalamount of a compound according to claim 1 or an N-oxide thereof or acomposition comprising said compound or an N-oxide thereof and apharmaceutically acceptable carrier.
 51. A method of treating anangiogenesis-mediated cell proliferative disease in a patient orinhibiting solid tumor growth in a patient, the method comprisingadministering to the patient in need thereof an effective therapeuticalamount of a compound according to claim 2 or an N-oxide thereof or acomposition comprising said compound or an N-oxide thereof and apharmaceutically acceptable carrier.
 52. A method of treating anangiogenesis-mediated cell proliferative disease in a patient orinhibiting solid tumor growth in a patient, the method comprisingadministering to the patient in need thereof an effective therapeuticalamount of a compound according to claim 3 or an N-oxide thereof or acomposition comprising said compound or an N-oxide thereof and apharmaceutically acceptable carrier.
 53. A method of treating anangiogenesis-mediated cell proliferative disease in a patient orinhibiting solid tumor growth in a patient, the method comprisingadministering to the patient in need thereof an effective therapeuticalamount of a compound according to claim 4 or an N-oxide thereof or acomposition comprising said compound or an N-oxide thereof and apharmaceutically acceptable carrier.
 54. A method of treating anangiogenesis-mediated cell proliferative disease in a patient orinhibiting solid tumor growth in a patient, the method comprisingadministering to the patient in need thereof an effective therapeuticalamount of a compound according to claim 5 or an N-oxide thereof or acomposition comprising said compound or an N-oxide thereof and apharmaceutically acceptable carrier.
 55. A method of treating anangiogenesis-mediated cell proliferative disease in a patient orinhibiting solid tumor growth in a patient, the method comprisingadministering to the patient in need thereof an effective therapeuticalamount of a compound according to claim 6 or an N-oxide thereof or acomposition comprising said compound or an N-oxide thereof and apharmaceutically acceptable carrier.